Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Dual Function Molecules and Processes in Cell Fate Decision 2.0

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Related Special Issue
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 28505

Share This Special Issue

Special Issue Editors

Prof. Dr. Michela Giuliano

E-Mail Website
Guest Editor

Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
Interests: cell death pathways; oncobiology; cancer; nutraceuticals; oxidative stress studies
Special Issues, Collections and Topics in MDPI journals

Dr. Sonia Emanuele

E-Mail Website
Guest Editor

Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
Interests: apoptosis; cancer; autophagy; epigenetics; HDAC inhibitors; cell stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent discoveries in cell biology have highlighted a number of molecules playing dual, opposite roles in different processes, including cell death, survival, proliferation, and differentiation.

This unusual behavior can be dependent on the cell environment, post-translational modifications, epigenetic regulation, and complex molecular network interactions. In some cases, hormetic responses can occur, as is the case with molecules such as reactive oxygen species (ROS), which are active as bio-modulators at low doses and are destructive at high concentrations. In addition, many cellular proteins exert a dual role in regulating cell fate determination, but the regulation mechanisms are not well known. Therefore, the molecular switches controlling this behavior remain to be elucidated.

This “Janus” role is not restricted to molecules but also involves cellular processes such as autophagy, a well characterized form of degradation of intracellular material that can be triggered either as a pro-survival response or as a cell death inducer.

The aim of this Special Issue is to focus on these double-faced molecules and processes participating in the regulation of cell fate to provide a critical analysis of different cell states and of the regulative mechanisms involved in opposite cell responses.

Prof. Michela Giuliano
Dr. Sonia Emanuele
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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.

Related Special Issue

Dual Function Molecules and Processes in Cell Fate Decision in International Journal of Molecular Sciences (11 articles)

Published Papers (7 papers)

Download All Papers

Research

Jump to: Review

16 pages, 6712 KiB

Open AccessArticle

Oncogenic BRAF and p53 Interplay in Melanoma Cells and the Effects of the HDAC Inhibitor ITF2357 (Givinostat)

by Adriana Celesia, Marzia Franzò, Diana Di Liberto, Marianna Lauricella, Daniela Carlisi, Antonella D’Anneo, Antonietta Notaro, Mario Allegra, Michela Giuliano and Sonia Emanuele

Int. J. Mol. Sci. 2023, 24(11), 9148; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119148 - 23 May 2023

Cited by 5 | Viewed by 1255

Abstract

Oncogenic BRAF mutations have been widely described in melanomas and promote tumour progression and chemoresistance. We previously provided evidence that the HDAC inhibitor ITF2357 (Givinostat) targets oncogenic BRAF in SK-MEL-28 and A375 melanoma cells. Here, we show that oncogenic BRAF localises to the nucleus of these cells, and the compound decreases BRAF levels in both the nuclear and cytosolic compartments. Although mutations in the tumour suppressor p53 gene are not equally frequent in melanomas compared to BRAF, the functional impairment of the p53 pathway may also contribute to melanoma development and aggressiveness. To understand whether oncogenic BRAF and p53 may cooperate, a possible interplay was considered in the two cell lines displaying a different p53 status, being p53 mutated into an oncogenic form in SK-MEL-28 and wild-type in A375 cells. Immunoprecipitation revealed that BRAF seems to preferentially interact with oncogenic p53. Interestingly, ITF2357 not only reduced BRAF levels but also oncogenic p53 levels in SK-MEL-28 cells. ITF2357 also targeted BRAF in A375 cells but not wild-type p53, which increased, most likely favouring apoptosis. Silencing experiments confirmed that the response to ITF2357 in BRAF-mutated cells depends on p53 status, thus providing a rationale for melanoma-targeted therapy. Full article

(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision 2.0)

► Show Figures

Figure 1

17 pages, 3432 KiB

Open AccessArticle

The Possible Connection of Two Dual Function Processes: The Relationship of Ferroptosis and the JNK Pathway

by Dóra Varga, Péter Hajdinák, Kinga Makk-Merczel and András Szarka

Int. J. Mol. Sci. 2022, 23(19), 11004; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911004 - 20 Sep 2022

Cited by 2 | Viewed by 1974

Abstract

Ferroptosis represents a typical process that has dual functions in cell fate decisions since the reduction and/or inhibition of ferroptosis is desirable for the therapies of diseases such as neurological disorders, localized ischemia-reperfusion, kidney injury, and hematological diseases, while the enhanced ferroptosis of cancer cells may benefit patients with cancer. The JNK pathway also has a real dual function in the fate of cells. Multiple factors suggest a potential link between the ferroptotic and JNK pathways; (i) both processes are ROS mediated; (ii) both can be inhibited by lipid peroxide scavengers; (iii) RAS mutations may play a role in the initiation of both pathways. We aimed to investigate the possible link between ferroptosis and the JNK pathway. Interestingly, JNK inhibitor co-treatment could enhance the cancer cytotoxic effect of the ferroptosis inducers in NRAS and KRAS mutation-harboring cells (HT-1080 and MIA PaCa-2). Since cancer’s cytotoxic effect from the JNK inhibitors could only be suspended by the ferroptosis inhibitors, and that sole JNK-inhibitor treatment did not affect cell viability, it seems that the JNK inhibitors “just” amplify the effect of the ferroptosis inducers. This cancer cell death amplifying effect of the JNK inhibitors could not be observed in other oxidative stress-driven cell deaths. Hence, it seems it is specific to ferroptosis. Finally, our results suggest that GSH content/depletion could be an important candidate for switching the anti-cancer effect of JNK inhibitors. Full article

(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision 2.0)

► Show Figures

Figure 1

18 pages, 3307 KiB

Open AccessArticle

How to Obtain a Mega-Intestine with Normal Morphology: In Silico Modelling of Postnatal Intestinal Growth in a Cd97-Transgenic Mouse

by Felix Hofmann, Torsten Thalheim, Karen Rother, Marianne Quaas, Christiane Kerner, Jens Przybilla, Gabriela Aust and Joerg Galle

Int. J. Mol. Sci. 2021, 22(14), 7345; https://doi.org/10.3390/ijms22147345 - 08 Jul 2021

Viewed by 2067

Abstract

Intestinal cylindrical growth peaks in mice a few weeks after birth, simultaneously with crypt fission activity. It nearly stops after weaning and cannot be reactivated later. Transgenic mice expressing Cd97/Adgre5 in the intestinal epithelium develop a mega-intestine with normal microscopic morphology in adult mice. Here, we demonstrate premature intestinal differentiation in Cd97/Adgre5 transgenic mice at both the cellular and molecular levels until postnatal day 14. Subsequently, the growth of the intestinal epithelium becomes activated and its maturation suppressed. These changes are paralleled by postnatal regulation of growth factors and by an increased expression of secretory cell markers, suggesting growth activation of non-epithelial tissue layers as the origin of enforced tissue growth. To understand postnatal intestinal growth mechanistically, we study epithelial fate decisions during this period with the use of a 3D individual cell-based computer model. In the model, the expansion of the intestinal stem cell (SC) population, a prerequisite for crypt fission, is largely independent of the tissue growth rate and is therefore not spontaneously adaptive. Accordingly, the model suggests that, besides the growth activation of non-epithelial tissue layers, the formation of a mega-intestine requires a released growth control in the epithelium, enabling accelerated SC expansion. The similar intestinal morphology in Cd97/Adgre5 transgenic and wild type mice indicates a synchronization of tissue growth and SC expansion, likely by a crypt density-controlled contact inhibition of growth of intestinal SC proliferation. The formation of a mega-intestine with normal microscopic morphology turns out to originate in changes of autonomous and conditional specification of the intestinal cell fate induced by the activation of Cd97/Adgre5. Full article

(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision 2.0)

► Show Figures

Figure 1

26 pages, 5790 KiB

Open AccessArticle

Dual Mechanisms of Metabolism and Gene Expression of the CCRF-CEM Leukemia Cells under Glucocorticoid Treatment

by George I. Lambrou, Theodoros Karakonstantakis, Spiros Vlahopoulos and Apostolos Zaravinos

Int. J. Mol. Sci. 2021, 22(11), 5889; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115889 - 31 May 2021

Viewed by 2692

Abstract

Background: Glucocorticoids play an essential part in anti-leukemic therapies, but resistance is a crucial event for the prognosis of the disease. Glucocorticoids influence the metabolic properties of leukemic cells. The inherent plasticity of clinically evolving cancer cells justifies the characterization of drug-induced early oncogenic pathways, which represent a likely source of detrimental secondary effects. Aim: The present work aims to investigate the effect of glucocorticoids in metabolic pathways in the CCRF-CEM leukemic cells. Metabolic factors and gene expression profiles were examined in order to unravel the possible mechanisms of the CCRF-CEM leukemic cell growth dynamics. Methods: CCRF-CEM cells were used as a model. Cells were treated with prednisolone with concentrations 0–700 μM. Cell culture supernatants were used for glucose, lactic acid, LDH, Na⁺, K⁺ and Ca⁺⁺ measurements. Cytotoxicity was determined with flow cytometry. Microarray analysis was performed using two different chips of 1.2 k and 4.8 k genes. Gene Ontology enrichment analysis was applied to find metabolism- and GC-related genes. Results: Higher prednisolone concentrations inhibited glucose uptake, without exhibiting any cytotoxic effects. Glucose consumption did not correlate with the total cell population, or the viable population, indicating that growth is not directly proportional to glucose consumption. Neither of the subpopulations, i.e., viable, necrotic, or apoptotic cells, contributed to this. Conclusions: Different types of leukemic cells seem to exhibit different patterns of glucose metabolism. Both resistant and sensitive CCRF-CEM cells followed the aerobic pathway of glycolysis. There is probably a rapid change in membrane permeability, causing a general shutdown towards everything that is outside the cell. This could in part also explain the observed resistance. Glucocorticoids do not enter the cell passively anymore and therefore no effects are observed. Based on our observations, ion concentrations are measurable factors both in vitro and in vivo, which makes them possible markers of glucocorticoid cytotoxic action. Full article

(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision 2.0)

► Show Figures

Figure 1

Review

Jump to: Research

19 pages, 1628 KiB

Open AccessReview

Friend or Foe: The Relativity of (Anti)oxidative Agents and Pathways

by András Szarka, Tamás Lőrincz and Péter Hajdinák

Int. J. Mol. Sci. 2022, 23(9), 5188; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095188 - 06 May 2022

Cited by 10 | Viewed by 2046

Abstract

An element, iron, a process, the generation of reactive oxygen species (ROS), and a molecule, ascorbate, were chosen in our study to show their dual functions and their role in cell fate decision. Iron is a critical component of numerous proteins involved in metabolism and detoxification. On the other hand, excessive amounts of free iron in the presence of oxygen can promote the production of potentially toxic ROS. They can result in persistent oxidative stress, which in turn can lead to damage and cell death. At the same time, ROS—at strictly regulated levels—are essential to maintaining the redox homeostasis, and they are engaged in many cellular signaling pathways, so their total elimination is not expedient. Ascorbate establishes a special link between ROS generation/elimination and cell death. At low concentrations, it behaves as an excellent antioxidant and has an important role in ROS elimination. However, at high concentrations, in the presence of transition metals such as iron, it drives the generation of ROS. In the term of the dual function of these molecules and oxidative stress, ascorbate/ROS-driven cell deaths are not necessarily harmful processes—they can be live-savers too. Full article

(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision 2.0)

► Show Figures

Figure 1

19 pages, 756 KiB

Open AccessReview

The Apoptosis Paradox in Cancer

by Ornella Morana, Will Wood and Christopher D. Gregory

Int. J. Mol. Sci. 2022, 23(3), 1328; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031328 - 25 Jan 2022

Cited by 102 | Viewed by 14127

Abstract

Cancer growth represents a dysregulated imbalance between cell gain and cell loss, where the rate of proliferating mutant tumour cells exceeds the rate of those that die. Apoptosis, the most renowned form of programmed cell death, operates as a key physiological mechanism that limits cell population expansion, either to maintain tissue homeostasis or to remove potentially harmful cells, such as those that have sustained DNA damage. Paradoxically, high-grade cancers are generally associated with high constitutive levels of apoptosis. In cancer, cell-autonomous apoptosis constitutes a common tumour suppressor mechanism, a property which is exploited in cancer therapy. By contrast, limited apoptosis in the tumour-cell population also has the potential to promote cell survival and resistance to therapy by conditioning the tumour microenvironment (TME)—including phagocytes and viable tumour cells—and engendering pro-oncogenic effects. Notably, the constitutive apoptosis-mediated activation of cells of the innate immune system can help orchestrate a pro-oncogenic TME and may also effect evasion of cancer treatment. Here, we present an overview of the implications of cell death programmes in tumour biology, with particular focus on apoptosis as a process with “double-edged” consequences: on the one hand, being tumour suppressive through deletion of malignant or pre-malignant cells, while, on the other, being tumour progressive through stimulation of reparatory and regenerative responses in the TME. Full article

(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision 2.0)

► Show Figures

Figure 1

22 pages, 1621 KiB

Open AccessReview

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

by Sonia Emanuele, Adriana Celesia, Antonella D’Anneo, Marianna Lauricella, Daniela Carlisi, Anna De Blasio and Michela Giuliano

Int. J. Mol. Sci. 2021, 22(15), 7963; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157963 - 26 Jul 2021

Cited by 19 | Viewed by 3200

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known transcription factor best recognised as one of the main regulators of the oxidative stress response. Beyond playing a crucial role in cell defence by transactivating cytoprotective genes encoding antioxidant and detoxifying enzymes, Nrf2 is also implicated in a wide network regulating anti-inflammatory response and metabolic reprogramming. Such a broad spectrum of actions renders the factor a key regulator of cell fate and a strategic player in the control of cell transformation and response to viral infections. The Nrf2 protective roles in normal cells account for its anti-tumour and anti-viral functions. However, Nrf2 overstimulation often occurs in tumour cells and a complex correlation of Nrf2 with cancer initiation and progression has been widely described. Therefore, if on one hand, Nrf2 has a dual role in cancer, on the other hand, the factor seems to display a univocal function in preventing inflammation and cytokine storm that occur under viral infections, specifically in coronavirus disease 19 (COVID-19). In such a variegate context, the present review aims to dissect the roles of Nrf2 in both cancer and COVID-19, two widespread diseases that represent a cause of major concern today. In particular, the review describes the molecular aspects of Nrf2 signalling in both pathological situations and the most recent findings about the advantages of Nrf2 inhibition or activation as possible strategies for cancer and COVID-19 treatment respectively. Full article

(This article belongs to the Special Issue Dual Function Molecules and Processes in Cell Fate Decision 2.0)

► Show Figures