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Cancers
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Targeting Calcium Signaling in Cancer Cells
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Targeting Calcium Signaling in Cancer Cells

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 78347

Special Issue Editors

Dr. Isaac Jardin

E-Mail Website
Guest Editor
Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Cáceres, Spain
Interests: Ca2+ signalling; pathophysiology and physiology of Ca2+ homeostasis; breast cancer; orai channels; STIMs proteins; TRP proteins; Ca2+ imaging and fluorimetry; Ca2+ proteins relationship
Dr. Jose Javier Lopez

E-Mail Website
Guest Editor
Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, 06006 Cáceres, Spain
Interests: physiology; pathophysiology; breast cancer; calcium homeostasis; store-operated calcium entry; STIM; orai; TRPC
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Cytosolic calcium homeostasis is a critical event in cell biology, because of the involvement of the ion in several physiological processes. There is a growing body of evidence demonstrating that some cancer cell types exhibit altered intracellular calcium homeostasis. Such unbalance is manifested either in the form of alteration in the gene/protein expression patterns, or as mutations of the molecules that mediate and fine-tune the process. Therefore, the interest of the scientific community to comprehend and unravel the relationship between calcium and cancer has expeditiously increased in the last two decades, and several key components of cytosolic calcium homeostasis have been suggested either as tumoral biomarkers or as targets for a number of cancers. 

The scope of this Special Issue of Cancers is to further expand our current knowledge on the relationship between intracellular calcium homeostasis and cancer. We welcome reviews and original research articles that explore, but are not limited to, the involvement of intracellular calcium in the molecular basis of different cancer types, like prostate cancer, lung cancer, breast cancer, and colon cancer, as well as the use of the mediators of calcium homeostasis as biomarkers or targets for cutting-edge therapies that could, eventually, leads to improvements in the diagnosis and treatment of cancer.

Dr. Isaac Jardin
Dr. Jose Javier Lopez
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cytosolic calcium homeostasis
  • cancer
  • calcium channels
  • tumoral biomarkers

Published Papers (17 papers)

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Research

Jump to: Review

28 pages, 6056 KiB  
Article
Hydrogen Sulfide-Evoked Intracellular Ca2+ Signals in Primary Cultures of Metastatic Colorectal Cancer Cells
by Pawan Faris, Federica Ferulli, Mauro Vismara, Matteo Tanzi, Sharon Negri, Agnese Rumolo, Kostantinos Lefkimmiatis, Marcello Maestri, Mudhir Shekha, Paolo Pedrazzoli, Gianni Francesco Guidetti, Daniela Montagna and Francesco Moccia
Cancers 2020, 12(11), 3338; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113338 - 11 Nov 2020
Cited by 15 | Viewed by 3276
Abstract
Exogenous administration of hydrogen sulfide (H2S) is emerging as an alternative anticancer treatment. H2S-releasing compounds have been shown to exert a strong anticancer effect by suppressing proliferation and/or inducing apoptosis in several cancer cell types, including colorectal carcinoma (CRC). [...] Read more.
Exogenous administration of hydrogen sulfide (H2S) is emerging as an alternative anticancer treatment. H2S-releasing compounds have been shown to exert a strong anticancer effect by suppressing proliferation and/or inducing apoptosis in several cancer cell types, including colorectal carcinoma (CRC). The mechanism whereby exogenous H2S affects CRC cell proliferation is yet to be clearly elucidated, but it could involve an increase in intracellular Ca2+ concentration ([Ca2+]i). Herein, we sought to assess for the first time whether (and how) sodium hydrosulfide (NaHS), one of the most widely employed H2S donors, induced intracellular Ca2+ signals in primary cultures of human metastatic CRC (mCRC) cells. We provided the evidence that NaHS induced extracellular Ca2+ entry in mCRC cells by activating the Ca2+-permeable channel Transient Receptor Potential Vanilloid 1 (TRPV1) followed by the Na+-dependent recruitment of the reverse-mode of the Na+/Ca2+ (NCX) exchanger. In agreement with these observations, TRPV1 protein was expressed and capsaicin, a selective TRPV1 agonist, induced Ca2+ influx by engaging both TRPV1 and NCX in mCRC cells. Finally, NaHS reduced mCRC cell proliferation, but did not promote apoptosis or aberrant mitochondrial depolarization. These data support the notion that exogenous administration of H2S may prevent mCRC cell proliferation through an increase in [Ca2+]i, which is triggered by TRPV1. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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20 pages, 5645 KiB  
Article
Blockage of Store-Operated Ca2+ Influx by Synta66 is Mediated by Direct Inhibition of the Ca2+ Selective Orai1 Pore
by Linda Waldherr, Adela Tiffner, Deepti Mishra, Matthias Sallinger, Romana Schober, Irene Frischauf, Tony Schmidt, Verena Handl, Peter Sagmeister, Manuel Köckinger, Isabella Derler, Muammer Üçal, Daniel Bonhenry, Silke Patz and Rainer Schindl
Cancers 2020, 12(10), 2876; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102876 - 06 Oct 2020
Cited by 29 | Viewed by 3530
Abstract
The Ca2+ sensor STIM1 and the Ca2+ channel Orai1 that form the store-operated Ca2+ (SOC) channel complex are key targets for drug development. Selective SOC inhibitors are currently undergoing clinical evaluation for the treatment of auto-immune and inflammatory responses and [...] Read more.
The Ca2+ sensor STIM1 and the Ca2+ channel Orai1 that form the store-operated Ca2+ (SOC) channel complex are key targets for drug development. Selective SOC inhibitors are currently undergoing clinical evaluation for the treatment of auto-immune and inflammatory responses and are also deemed promising anti-neoplastic agents since SOC channels are linked with enhanced cancer cell progression. Here, we describe an investigation of the site of binding of the selective inhibitor Synta66 to the SOC channel Orai1 using docking and molecular dynamics simulations, and live cell recordings. Synta66 binding was localized to the extracellular site close to the transmembrane (TM)1 and TM3 helices and the extracellular loop segments, which, importantly, are adjacent to the Orai1-selectivity filter. Synta66-sensitivity of the Orai1 pore was, in fact, diminished by both Orai1 mutations affecting Ca2+ selectivity and permeation of Na+ in the absence of Ca2+. Synta66 also efficiently blocked SOC in three glioblastoma cell lines but failed to interfere with cell viability, division and migration. These experiments provide new structural and functional insights into selective drug inhibition of the Orai1 Ca2+ channel by a high-affinity pore blocker. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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22 pages, 3320 KiB  
Article
Calcium Signaling Alterations Caused by Epigenetic Mechanisms in Pancreatic Cancer: From Early Markers to Prognostic Impact
by Cleandra Gregório, Sheila Coelho Soares-Lima, Bárbara Alemar, Mariana Recamonde-Mendoza, Diego Camuzi, Paulo Thiago de Souza-Santos, Raquel Rivero, Simone Machado, Alessandro Osvaldt, Patricia Ashton-Prolla and Luis Felipe Ribeiro Pinto
Cancers 2020, 12(7), 1735; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071735 - 30 Jun 2020
Cited by 14 | Viewed by 3592
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality rates. PDAC initiation and progression are promoted by genetic and epigenetic dysregulation. Here, we aimed to characterize the PDAC DNA methylome in search of novel altered pathways associated with tumor development. We [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality rates. PDAC initiation and progression are promoted by genetic and epigenetic dysregulation. Here, we aimed to characterize the PDAC DNA methylome in search of novel altered pathways associated with tumor development. We examined the genome-wide DNA methylation profile of PDAC in an exploratory cohort including the comparative analyses of tumoral and non-tumoral pancreatic tissues (PT). Pathway enrichment analysis was used to choose differentially methylated (DM) CpGs with potential biological relevance. Additional samples were used in a validation cohort. DNA methylation impact on gene expression and its association with overall survival (OS) was investigated from PDAC TCGA (The Cancer Genome Atlas) data. Pathway analysis revealed DM genes in the calcium signaling pathway that is linked to the key pathways in pancreatic carcinogenesis. DNA methylation was frequently correlated with expression, and a subgroup of calcium signaling genes was associated with OS, reinforcing its probable phenotypic effect. Cluster analysis of PT samples revealed that some of the methylation alterations observed in the Calcium signaling pathway seemed to occur early in the carcinogenesis process, a finding that may open new insights about PDAC tumor biology. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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15 pages, 2895 KiB  
Article
Calcium Release-Activated Calcium (CRAC) Channel Inhibition Suppresses Pancreatic Ductal Adenocarcinoma Cell Proliferation and Patient-Derived Tumor Growth
by Husain Yar Khan, Gabriel B. Mpilla, Rachel Sexton, Srikant Viswanadha, Kumar V. Penmetsa, Amro Aboukameel, Maria Diab, Mandana Kamgar, Mohammed Najeeb Al-Hallak, Mark Szlaczky, Anteneh Tesfaye, Steve Kim, Philip A. Philip, Ramzi M. Mohammad and Asfar S. Azmi
Cancers 2020, 12(3), 750; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030750 - 22 Mar 2020
Cited by 24 | Viewed by 3465
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains an unmet clinical problem in urgent need of newer molecularly driven treatment modalities. Calcium signals, particularly those associated with calcium release-activated calcium (CRAC) channels, are known to influence the development, growth, and metastasis of many cancers. This is [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) remains an unmet clinical problem in urgent need of newer molecularly driven treatment modalities. Calcium signals, particularly those associated with calcium release-activated calcium (CRAC) channels, are known to influence the development, growth, and metastasis of many cancers. This is the first study investigating the impact of CRAC channel inhibition on PDAC cell lines and patient-derived tumor models. PDAC cell lines were exposed to a novel CRAC channel inhibitor, RP4010, in the presence or absence of standard of care drugs such as gemcitabine and nab-paclitaxel. The in vivo efficacy of RP4010 was evaluated in a hyaluronan-positive PDAC patient-derived xenograft (PDx) in the presence or absence of chemotherapeutic agents. Treatment of PDAC cell lines with single-agent RP4010 decreased cell growth, while the combination with gemcitabine/nab-paclitaxel exhibited synergy at certain dose combinations. Molecular analysis showed that RP4010 modulated the levels of markers associated with CRAC channel signaling pathways. Further, the combination treatment was observed to accentuate the effect of RP4010 on molecular markers of CRAC signaling. Anti-tumor activity of RP4010 was enhanced in the presence of gemcitabine/nab-paclitaxel in a PDAC PDx model. Our study indicates that targeting CRAC channel could be a viable therapeutic option in PDAC that warrants further clinical evaluation. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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27 pages, 4522 KiB  
Article
NO1, a New Sigma 2 Receptor/TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines
by Carlos Cantonero, Pedro Javier Camello, Carmen Abate, Francesco Berardi, Gines Maria Salido, Juan Antonio Rosado and Pedro C. Redondo
Cancers 2020, 12(2), 257; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020257 - 21 Jan 2020
Cited by 27 | Viewed by 4177
Abstract
(1) Background: The structure of the Sigma 2 receptor/TMEM97 (σ2RTMEM97) has recently been reported. (2, 3) Methods and results: We used genetic and biochemical approaches to identify the molecular mechanism downstream of σ2R/TMEM97. The novel σ2R/TMEM97 fluorescent ligand, NO1, reduced the proliferation and [...] Read more.
(1) Background: The structure of the Sigma 2 receptor/TMEM97 (σ2RTMEM97) has recently been reported. (2, 3) Methods and results: We used genetic and biochemical approaches to identify the molecular mechanism downstream of σ2R/TMEM97. The novel σ2R/TMEM97 fluorescent ligand, NO1, reduced the proliferation and survival of the triple negative breast cancer cell lines (TNBC: MDA-MB-231 and MDA-MB-468 cell lines), due to NO1-induced apoptosis. Greater bioaccumulation and faster uptake of NO1 in MDA-MB-231 cells compared to MCF10A or MCF7 cell lines were also shown. Accordingly, elevated σ2R/TMEM97 expression was confirmed by Western blotting. In contrast to NO1, other σ2R/TMEM97 ligands, such as SM21 and PB28, enhanced MDA-MB-231 cell proliferation and migration. Store-operated calcium entry (SOCE) is crucial for different cancer hallmarks. Here, we show that NO1, but not other σ2R/TMEM97 ligands, reduced SOCE in MDA-MB-231 cells. Similarly, TMEM97 silencing in MDA-MB-231 cells also impaired SOCE. NO1 administration downregulated STIM1-Orai1 interaction, probably by impairing the positive regulatory effect of σ2R/TMEM97 on STIM1, as we were unable to detect interaction with Orai1. (4) Conclusion: σ2R/TMEM97 is a key protein for the survival of triple negative breast cancer cells by promoting SOCE; therefore, NO1 may become a good pharmacological tool to avoid their proliferation. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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22 pages, 3488 KiB  
Article
Plasma Membrane Ca2+ ATPase Isoform 4 (PMCA4) Has an Important Role in Numerous Hallmarks of Pancreatic Cancer
by Pishyaporn Sritangos, Eduardo Pena Alarcon, Andrew D. James, Ahlam Sultan, Daniel A. Richardson and Jason I. E. Bruce
Cancers 2020, 12(1), 218; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010218 - 16 Jan 2020
Cited by 14 | Viewed by 4648
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to standard treatments leading to poor patient survival. The expression of plasma membrane calcium ATPase-4 (PMCA4) is reported to modulate key cancer hallmarks including cell migration, growth, and apoptotic resistance. Data-mining revealed that PMCA4 was over-expressed [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to standard treatments leading to poor patient survival. The expression of plasma membrane calcium ATPase-4 (PMCA4) is reported to modulate key cancer hallmarks including cell migration, growth, and apoptotic resistance. Data-mining revealed that PMCA4 was over-expressed in pancreatic ductal adenocarcinoma (PDAC) tumors which correlated with poor patient survival. Western blot and RT-qPCR revealed that MIA PaCa-2 cells almost exclusively express PMCA4 making these a suitable cellular model of PDAC with poor patient survival. Knockdown of PMCA4 in MIA PaCa-2 cells (using siRNA) reduced cytosolic Ca2+ ([Ca2+]i) clearance, cell migration, and sensitized cells to apoptosis, without affecting cell growth. Knocking down PMCA4 had minimal effects on numerous metabolic parameters (as assessed using the Seahorse XF analyzer). In summary, this study provides the first evidence that PMCA4 is over-expressed in PDAC and plays a role in cell migration and apoptotic resistance in MIA PaCa-2 cells. This suggests that PMCA4 may offer an attractive novel therapeutic target in PDAC. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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14 pages, 2799 KiB  
Article
A Novel Calcium-Mediated EMT Pathway Controlled by Lipids: An Opportunity for Prostate Cancer Adjuvant Therapy
by Sandy Figiel, Fanny Bery, Aurélie Chantôme, Delphine Fontaine, Côme Pasqualin, Véronique Maupoil, Isabelle Domingo, Roseline Guibon, Franck Bruyère, Marie Potier-Cartereau, Christophe Vandier, Gaëlle Fromont and Karine Mahéo
Cancers 2019, 11(11), 1814; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111814 - 18 Nov 2019
Cited by 26 | Viewed by 3014
Abstract
The composition of periprostatic adipose tissue (PPAT) has been shown to play a role in prostate cancer (PCa) progression. We recently reported an inverse association between PCa aggressiveness and elevated PPAT linoleic acid (LA) and eicosapentaenoic acid (EPA) content. In the present study, [...] Read more.
The composition of periprostatic adipose tissue (PPAT) has been shown to play a role in prostate cancer (PCa) progression. We recently reported an inverse association between PCa aggressiveness and elevated PPAT linoleic acid (LA) and eicosapentaenoic acid (EPA) content. In the present study, we identified a new signaling pathway with a positive feedback loop between the epithelial-to-mesenchymal transition (EMT) transcription factor Zeb1 and the Ca2+-activated K+ channel SK3, which leads to an amplification of Ca2+ entry and cellular migration. Using in vitro experiments and ex vivo cultures of human PCa slices, we demonstrated that LA and EPA exert anticancer effects, by modulating Ca2+ entry, which was involved in Zeb1 regulation and cancer cellular migration. This functional approach using human prostate tumors highlights the clinical relevance of our observations, and may allow us to consider the possibility of targeting cancer spread by altering the lipid microenvironment. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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24 pages, 4700 KiB  
Article
Adenylyl Cyclase Type 8 Overexpression Impairs Phosphorylation-Dependent Orai1 Inactivation and Promotes Migration in MDA-MB-231 Breast Cancer Cells
by Jose Sanchez-Collado, Jose J. Lopez, Isaac Jardin, Pedro J. Camello, Debora Falcon, Sergio Regodon, Gines M. Salido, Tarik Smani and Juan A. Rosado
Cancers 2019, 11(11), 1624; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111624 - 23 Oct 2019
Cited by 32 | Viewed by 3363
Abstract
Orai1 plays a major role in store-operated Ca2+ entry (SOCE) in triple-negative breast cancer (TNBC) cells. This channel is inactivated via different mechanisms, including protein kinase C (PKC) and protein kinase A (PKA)-dependent phosphorylation at Ser-27 and Ser-30 or Ser-34, respectively, which [...] Read more.
Orai1 plays a major role in store-operated Ca2+ entry (SOCE) in triple-negative breast cancer (TNBC) cells. This channel is inactivated via different mechanisms, including protein kinase C (PKC) and protein kinase A (PKA)-dependent phosphorylation at Ser-27 and Ser-30 or Ser-34, respectively, which shapes the Ca2+ responses to agonists. The Ca2+ calmodulin-activated adenylyl cyclase type 8 (AC8) was reported to interact directly with Orai1, thus mediating a dynamic interplay between the Ca2+- and cyclic adenosine monophosphate (cAMP)-dependent signaling pathways. Here, we show that the breast cancer cell lines MCF7 and MDA-MB-231 exhibit enhanced expression of Orai1 and AC8 as compared to the non-tumoral breast epithelial MCF10A cell line. In these cells, AC8 interacts with the Orai1α variant in a manner that is not regulated by Orai1 phosphorylation. AC8 knockdown in MDA-MB-231 cells, using two different small interfering RNAs (siRNAs), attenuates thapsigargin (TG)-induced Ca2+ entry and also Ca2+ influx mediated by co-expression of Orai1 and the Orai1-activating small fragment (OASF) of STIM1 (stromal interaction molecule-1). Conversely, AC8 overexpression enhances SOCE, as well as Ca2+ entry, in cells co-expressing Orai1 and OASF. In MDA-MB-231 cells, we found that AC8 overexpression reduces the Orai1 phosphoserine content, thus suggesting that AC8 interferes with Orai1 serine phosphorylation, which takes place at residues located in the AC8-binding site. Consistent with this, the subset of Orai1 associated with AC8 in naïve MDA-MB-231 cells is not phosphorylated in serine residues in contrast to the AC8-independent Orai1 subset. AC8 expression knockdown attenuates migration of MCF7 and MDA-MB-231 cells, while this maneuver has no effect in the MCF10A cell line, which is likely attributed to the low expression of AC8 in these cells. We found that AC8 is required for FAK (focal adhesion kinase) phosphorylation in MDA-MB-231 cells, which might explain its role in cell migration. Finally, we found that AC8 is required for TNBC cell proliferation. These findings indicate that overexpression of AC8 in breast cancer MDA-MB-231 cells impairs the phosphorylation-dependent Orai1 inactivation, a mechanism that might support the enhanced ability of these cells to migrate. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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Review

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32 pages, 4340 KiB  
Review
Targeting Ca2+ Signaling in the Initiation, Promotion and Progression of Hepatocellular Carcinoma
by Eunus S. Ali, Grigori Y. Rychkov and Greg J. Barritt
Cancers 2020, 12(10), 2755; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102755 - 24 Sep 2020
Cited by 11 | Viewed by 3706
Abstract
Hepatocellular carcinoma (HCC) is a considerable health burden worldwide and a major contributor to cancer-related deaths. HCC is often not noticed until at an advanced stage where treatment options are limited and current systemic drugs can usually only prolong survival for a short [...] Read more.
Hepatocellular carcinoma (HCC) is a considerable health burden worldwide and a major contributor to cancer-related deaths. HCC is often not noticed until at an advanced stage where treatment options are limited and current systemic drugs can usually only prolong survival for a short time. Understanding the biology and pathology of HCC is a challenge, due to the cellular and anatomic complexities of the liver. While not yet fully understood, liver cancer stem cells play a central role in the initiation and progression of HCC and in resistance to drugs. There are approximately twenty Ca2+-signaling proteins identified as potential targets for therapeutic treatment at different stages of HCC. These potential targets include inhibition of the self-renewal properties of liver cancer stem cells; HCC initiation and promotion by hepatitis B and C and non-alcoholic fatty liver disease (principally involving reduction of reactive oxygen species); and cell proliferation, tumor growth, migration and metastasis. A few of these Ca2+-signaling pathways have been identified as targets for natural products previously known to reduce HCC. Promising Ca2+-signaling targets include voltage-operated Ca2+ channel proteins (liver cancer stem cells), inositol trisphosphate receptors, store-operated Ca2+ entry, TRP channels, sarco/endoplasmic reticulum (Ca2++Mg2+) ATP-ase and Ca2+/calmodulin-dependent protein kinases. However, none of these Ca2+-signaling targets has been seriously studied any further than laboratory research experiments. The future application of more systematic studies, including genomics, gene expression (RNA-seq), and improved knowledge of the fundamental biology and pathology of HCC will likely reveal new Ca2+-signaling protein targets and consolidate priorities for those already identified. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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Graphical abstract

19 pages, 1521 KiB  
Review
Mitochondrial Metabolism, Contact Sites and Cellular Calcium Signaling: Implications for Tumorigenesis
by Roberta Peruzzo, Roberto Costa, Magdalena Bachmann, Luigi Leanza and Ildikò Szabò
Cancers 2020, 12(9), 2574; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092574 - 10 Sep 2020
Cited by 20 | Viewed by 3618
Abstract
Mitochondria are organelles that are mainly involved in the generation of ATP by cellular respiration. In addition, they modulate several intracellular functions, ranging from cell proliferation and differentiation to cell death. Importantly, mitochondria are social and can interact with other organelles, such as [...] Read more.
Mitochondria are organelles that are mainly involved in the generation of ATP by cellular respiration. In addition, they modulate several intracellular functions, ranging from cell proliferation and differentiation to cell death. Importantly, mitochondria are social and can interact with other organelles, such as the Endoplasmic Reticulum, lysosomes and peroxisomes. This symbiotic relationship gives advantages to both partners in regulating some of their functions related to several aspects of cell survival, metabolism, sensitivity to cell death and metastasis, which can all finally contribute to tumorigenesis. Moreover, growing evidence indicates that modulation of the length and/or numbers of these contacts, as well as of the distance between the two engaged organelles, impacts both on their function as well as on cellular signaling. In this review, we discuss recent advances in the field of contacts and communication between mitochondria and other intracellular organelles, focusing on how the tuning of mitochondrial function might impact on both the interaction with other organelles as well as on intracellular signaling in cancer development and progression, with a special focus on calcium signaling. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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34 pages, 6170 KiB  
Review
Targeting the Calcium Signalling Machinery in Cancer
by Jason I. E. Bruce and Andrew D. James
Cancers 2020, 12(9), 2351; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092351 - 20 Aug 2020
Cited by 34 | Viewed by 5205
Abstract
Cancer is caused by excessive cell proliferation and a propensity to avoid cell death, while the spread of cancer is facilitated by enhanced cellular migration, invasion, and vascularization. Cytosolic Ca2+ is central to each of these important processes, yet to date, there [...] Read more.
Cancer is caused by excessive cell proliferation and a propensity to avoid cell death, while the spread of cancer is facilitated by enhanced cellular migration, invasion, and vascularization. Cytosolic Ca2+ is central to each of these important processes, yet to date, there are no cancer drugs currently being used clinically, and very few undergoing clinical trials, that target the Ca2+ signalling machinery. The aim of this review is to highlight some of the emerging evidence that targeting key components of the Ca2+ signalling machinery represents a novel and relatively untapped therapeutic strategy for the treatment of cancer. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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29 pages, 2150 KiB  
Review
Altered Organelle Calcium Transport in Ovarian Physiology and Cancer
by Laura Caravia, Cristina Elena Staicu, Beatrice Mihaela Radu, Carmen Elena Condrat, Dragoș Crețoiu, Nicolae Bacalbașa, Nicolae Suciu, Sanda Maria Crețoiu and Silviu Cristian Voinea
Cancers 2020, 12(8), 2232; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082232 - 10 Aug 2020
Cited by 6 | Viewed by 3988
Abstract
Calcium levels have a huge impact on the physiology of the female reproductive system, in particular, of the ovaries. Cytosolic calcium levels are influenced by regulatory proteins (i.e., ion channels and pumps) localized in the plasmalemma and/or in the endomembranes of membrane-bound organelles. [...] Read more.
Calcium levels have a huge impact on the physiology of the female reproductive system, in particular, of the ovaries. Cytosolic calcium levels are influenced by regulatory proteins (i.e., ion channels and pumps) localized in the plasmalemma and/or in the endomembranes of membrane-bound organelles. Imbalances between plasma membrane and organelle-based mechanisms for calcium regulation in different ovarian cell subtypes are contributing to ovarian pathologies, including ovarian cancer. In this review, we focused our attention on altered calcium transport and its role as a contributor to tumor progression in ovarian cancer. The most important proteins described as contributing to ovarian cancer progression are inositol trisphosphate receptors, ryanodine receptors, transient receptor potential channels, calcium ATPases, hormone receptors, G-protein-coupled receptors, and/or mitochondrial calcium uniporters. The involvement of mitochondrial and/or endoplasmic reticulum calcium imbalance in the development of resistance to chemotherapeutic drugs in ovarian cancer is also discussed, since Ca2+ channels and/or pumps are nowadays regarded as potential therapeutic targets and are even correlated with prognosis. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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38 pages, 1667 KiB  
Review
Friend or Foe: S100 Proteins in Cancer
by Chantal Allgöwer, Anna-Laura Kretz, Silvia von Karstedt, Mathias Wittau, Doris Henne-Bruns and Johannes Lemke
Cancers 2020, 12(8), 2037; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082037 - 24 Jul 2020
Cited by 75 | Viewed by 8243
Abstract
S100 proteins are widely expressed small molecular EF-hand calcium-binding proteins of vertebrates, which are involved in numerous cellular processes, such as Ca2+ homeostasis, proliferation, apoptosis, differentiation, and inflammation. Although the complex network of S100 signalling is by far not fully deciphered, several [...] Read more.
S100 proteins are widely expressed small molecular EF-hand calcium-binding proteins of vertebrates, which are involved in numerous cellular processes, such as Ca2+ homeostasis, proliferation, apoptosis, differentiation, and inflammation. Although the complex network of S100 signalling is by far not fully deciphered, several S100 family members could be linked to a variety of diseases, such as inflammatory disorders, neurological diseases, and also cancer. The research of the past decades revealed that S100 proteins play a crucial role in the development and progression of many cancer types, such as breast cancer, lung cancer, and melanoma. Hence, S100 family members have also been shown to be promising diagnostic markers and possible novel targets for therapy. However, the current knowledge of S100 proteins is limited and more attention to this unique group of proteins is needed. Therefore, this review article summarises S100 proteins and their relation in different cancer types, while also providing an overview of novel therapeutic strategies for targeting S100 proteins for cancer treatment. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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14 pages, 1146 KiB  
Review
Mechanosensitive Piezo Channels in Cancer: Focus on altered Calcium Signaling in Cancer Cells and in Tumor Progression
by Dario De Felice and Alessandro Alaimo
Cancers 2020, 12(7), 1780; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071780 - 03 Jul 2020
Cited by 66 | Viewed by 10396
Abstract
Mechanotransduction, the translation of mechanical stimuli into biological signals, is a crucial mechanism involved in the function of fundamentally all cell types. In many solid tumors, the malignant transformation is often associated with drastic changes in cell mechanical features. Extracellular matrix stiffness, invasive [...] Read more.
Mechanotransduction, the translation of mechanical stimuli into biological signals, is a crucial mechanism involved in the function of fundamentally all cell types. In many solid tumors, the malignant transformation is often associated with drastic changes in cell mechanical features. Extracellular matrix stiffness, invasive growth, and cell mobility are just a few hallmarks present in cancer cells that, by inducing mechanical stimuli, create positive feedbacks promoting cancer development. Among the molecular players involved in these pathophysiological processes, the mechanosensitive Ca2+-permeable Piezo channels have emerged as major transducers of mechanical stress into Ca2+ dependent signals. Piezo channels are overexpressed in several cancers, such as in breast, gastric, and bladder, whereas their downregulation has been described in other cancers. Still, the roles of mechanosensitive Piezos in cancer are somewhat puzzling. In this review, we summarize the current knowledge on the pathophysiological roles of these Ca2+-permeable channels, with special emphasis on their functional involvement in different cancer types progression. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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27 pages, 2504 KiB  
Review
Role of Calcium Signaling in Prostate Cancer Progression: Effects on Cancer Hallmarks and Bone Metastatic Mechanisms
by Juan A. Ardura, Luis Álvarez-Carrión, Irene Gutiérrez-Rojas and Verónica Alonso
Cancers 2020, 12(5), 1071; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051071 - 25 Apr 2020
Cited by 38 | Viewed by 7231
Abstract
Advanced prostate cancers that progress to tumor metastases are often considered incurable or difficult to treat. The etiology of prostate cancers is multi-factorial. Among other factors, de-regulation of calcium signals in prostate tumor cells mediates several pathological dysfunctions associated with tumor progression. Calcium [...] Read more.
Advanced prostate cancers that progress to tumor metastases are often considered incurable or difficult to treat. The etiology of prostate cancers is multi-factorial. Among other factors, de-regulation of calcium signals in prostate tumor cells mediates several pathological dysfunctions associated with tumor progression. Calcium plays a relevant role on tumor cell death, proliferation, motility-invasion and tumor metastasis. Calcium controls molecular factors and signaling pathways involved in the development of prostate cancer and its progression. Such factors and pathways include calcium channels and calcium-binding proteins. Nevertheless, the involvement of calcium signaling on prostate cancer predisposition for bone tropism has been relatively unexplored. In this regard, a diversity of mechanisms triggers transient accumulation of intracellular calcium in prostate cancer cells, potentially favoring bone metastases development. New therapies for the treatment of prostate cancer include compounds characterized by potent and specific actions that target calcium channels/transporters or pumps. These novel drugs for prostate cancer treatment encompass calcium-ATPase inhibitors, voltage-gated calcium channel inhibitors, transient receptor potential (TRP) channel regulators or Orai inhibitors. This review details the latest results that have evaluated the relationship between calcium signaling and progression of prostate cancer, as well as potential therapies aiming to modulate calcium signaling in prostate tumor progression. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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13 pages, 1117 KiB  
Review
T-Type Calcium Channels: A Potential Novel Target in Melanoma
by Carla Barceló, Pol Sisó, Oscar Maiques, Inés de la Rosa, Rosa M. Martí and Anna Macià
Cancers 2020, 12(2), 391; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020391 - 08 Feb 2020
Cited by 14 | Viewed by 3452
Abstract
T-type calcium channels (TTCCs) are overexpressed in several cancers. In this review, we summarize the recent advances and new insights into TTCC biology, tumor progression, and prognosis biomarker and therapeutic potential in the melanoma field. We describe a novel correlation between the Cav3.1 [...] Read more.
T-type calcium channels (TTCCs) are overexpressed in several cancers. In this review, we summarize the recent advances and new insights into TTCC biology, tumor progression, and prognosis biomarker and therapeutic potential in the melanoma field. We describe a novel correlation between the Cav3.1 isoform and the increased basal autophagy in BRAFV600E-mutant melanomas and after acquired resistance to BRAF inhibitors. Indeed, TTCC blockers reduce melanoma cell viability and migration/invasion in vitro and tumor growth in mice xenografts in both BRAF-inhibitor-sensitive and -resistant scenarios. These studies open a new, promising therapeutic approach for disseminated melanoma and improved treatment in BRAFi relapsed melanomas, but further validation and clinical trials are needed for it to become a real therapeutic option. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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10 pages, 655 KiB  
Review
Targeting Calcium Signalling in Malignant Mesothelioma
by Simona Martinotti, Mauro Patrone, Francesco Moccia and Elia Ranzato
Cancers 2019, 11(12), 1839; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121839 - 21 Nov 2019
Cited by 5 | Viewed by 2275
Abstract
Calcium ions (Ca2+) are central in cancer development and growth, serving as a major signaling system determining the cell’s fate. Therefore, the investigation of the functional roles of ion channels in cancer development may identify novel approaches for determining tumor prognosis. [...] Read more.
Calcium ions (Ca2+) are central in cancer development and growth, serving as a major signaling system determining the cell’s fate. Therefore, the investigation of the functional roles of ion channels in cancer development may identify novel approaches for determining tumor prognosis. Malignant mesothelioma is an aggressive cancer that develops from the serosal surface of the body, strictly related to asbestos exposure. The treatment of malignant mesothelioma is complex and the survival outcomes, rather than the overall survival data are, to date, disappointedly daunting. Nevertheless, conventional chemotherapy is almost ineffective. The alteration in the expression and/or activity of Ca2+ permeable ion channels seems to be characteristic of mesothelioma cells. In this review, we explore the involvement of the Ca2+toolkit in this disease. Moreover, the established sensitivity of some Ca2+channels to selective pharmacological modulators makes them interesting targets for mesothelioma cancer therapy. Full article
(This article belongs to the Special Issue Targeting Calcium Signaling in Cancer Cells)
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