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

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 10647

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Dr. Claudio Favre

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Guest Editor

Division of Pediatric Oncology/Hematology, Meyer University Children’s Hospital, 50139 Florence, Italy
Interests: β-adrenergic receptors in pediatric cancer; blood malignancy; innovative therapy nutraceutical approach in cancer therapy
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Dear Colleagues,

Mitochondria in cancer cells utilize a broad range of metabolic pathways such as glucose oxidation, fatty acid β-oxidation (fao), and glutamine oxidation to fuel the electron transport chain (etc.) for ATP production. Many studies have shown that fatty acid can serve as a major energy source for different cancers. In addition, other tumors exhibit increased utilization of oxidative phosphorylation (OXPHOS) for ATP production compared to normal tissue. Moreover, glutamine oxidation, usually driven by the oncogene MYC, plays a critical role in energy production and promoting tumor growth in multiple cancer types. The metabolic phenotype is not necessarily uniform across the cell population in the tumor or in the different cells of the microenvironment.

Mitochondria in most tumors are not defective in their ability to carry out OXPHOS even if aerobic glycolysis has been reported as the dominant metabolic phenotype in cancer cells for a long time. Mitochondrial energy reprogramming is also involved in the regulation of oncogenic pathways via mitochondria–nucleus retrograde signaling and post-translational modification of oncoproteins. In addition, neoplastic mitochondria can engage in crosstalk with the tumor microenvironment. Mitochondria can change their activity in response to external stimuli for better survival of cancer cells, leading to a very plastic phenotype.

Therefore, an enhanced understanding of the importance and plasticity of mitochondria in metabolic reprogramming of cancer cells has become a novel hallmark of cancer.

Dr. Claudio Favre
Guest Editor

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Keywords

mitochondria
metabolism
stem cell
microenvironment

Published Papers (4 papers)

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Research

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14 pages, 2496 KiB

Open AccessArticle

Arsenic Trioxide and Venetoclax Synergize against AML Progenitors by ROS Induction and Inhibition of Nrf2 Activation

by Dinh Hoa Hoang, Ralf Buettner, Melissa Valerio, Lucy Ghoda, Bin Zhang, Ya-Huei Kuo, Steven T. Rosen, John Burnett, Guido Marcucci, Vinod Pullarkat and Le Xuan Truong Nguyen

Int. J. Mol. Sci. 2022, 23(12), 6568; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126568 - 12 Jun 2022

Cited by 10 | Viewed by 2501

Abstract

Venetoclax (VEN) in combination with hypomethylating agents induces disease remission in patients with de novo AML, however, most patients eventually relapse. AML relapse is attributed to the persistence of drug-resistant leukemia stem cells (LSCs). LSCs need to maintain low intracellular levels of reactive oxygen species (ROS). Arsenic trioxide (ATO) induces apoptosis via upregulation of ROS-induced stress to DNA-repair mechanisms. Elevated ROS levels can trigger the Nrf2 antioxidant pathway to counteract the effects of high ROS levels. We hypothesized that ATO and VEN synergize in targeting LSCs through ROS induction by ATO and the known inhibitory effect of VEN on the Nrf2 antioxidant pathway. Using cell fractionation, immunoprecipitation, RNA-knockdown, and fluorescence assays we found that ATO activated nuclear translocation of Nrf2 and increased transcription of antioxidant enzymes, thereby attenuating the induction of ROS by ATO. VEN disrupted ATO-induced Nrf2 translocation and augmented ATO-induced ROS, thus enhancing apoptosis in LSCs. Using metabolic assays and electron microscopy, we found that the ATO+VEN combination decreased mitochondrial membrane potential, mitochondria size, fatty acid oxidation and oxidative phosphorylation, all of which enhanced apoptosis of LSCs derived from both VEN-sensitive and VEN-resistant AML primary cells. Our results indicate that ATO and VEN cooperate in inducing apoptosis of LSCs through potentiation of ROS induction, suggesting ATO+VEN is a promising regimen for treatment of VEN-sensitive and -resistant AML. Full article

(This article belongs to the Special Issue Mitochondrial Plasticity in Cancer)

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18 pages, 3474 KiB

Open AccessArticle

NSAIDs Induce Proline Dehydrogenase/Proline Oxidase-Dependent and Independent Apoptosis in MCF7 Breast Cancer Cells

by Adam Kazberuk, Magda Chalecka, Jerzy Palka, Katarzyna Bielawska and Arkadiusz Surazynski

Int. J. Mol. Sci. 2022, 23(7), 3813; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073813 - 30 Mar 2022

Cited by 2 | Viewed by 2205

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are considered in cancer therapy for their inhibitory effect on cyclooxygenase-2 (COX-2), which is overexpressed in most cancers. However, we found that NSAIDs as ligands of peroxisome proliferator-activated receptor-γ (PPARγ)-induced apoptosis independent of the COX-2 inhibition, and the process was mediated through activation of proline dehydrogenase/proline oxidase (PRODH/POX)-dependent generation of reactive oxygen species (ROS). This mitochondrial enzyme converts proline to ∆1-pyrroline-5-carboxylate (P5C) during which ATP or ROS is generated. To confirm the role of PRODH/POX in the mechanism of NSAID-induced apoptosis we obtained an MCF7 CRISPR/Cas9 PRODH/POX knockout breast cancer cell model (MCF7^POK-KO). Interestingly, the studied NSAIDs (indomethacin and diclofenac) in MCF7^POK-KO cells contributed to a more pronounced pro-apoptotic phenotype of the cells than in PRODH/POX-expressing MCF7 cells. The observed effect was independent of ROS generation, but it was related to the energetic disturbances in the cells as shown by an increase in the expression of AMPKα (sensor of cell energy status), GLUD1/2 (proline producing enzyme from glutamate), prolidase (proline releasing enzyme), PPARδ (growth supporting transcription factor) and a decrease in the expression of proline cycle enzymes (PYCR1, PYCRL), mammalian target of rapamycin (mTOR), and collagen biosynthesis (the main proline utilizing process). The data provide evidence that the studied NSAIDs induce PRODH/POX-dependent and independent apoptosis in MCF7 breast cancer cells. Full article

(This article belongs to the Special Issue Mitochondrial Plasticity in Cancer)

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19 pages, 1325 KiB

Open AccessArticle

Metabolic Reprogramming in Response to Alterations of Mitochondrial DNA and Mitochondrial Dysfunction in Gastric Adenocarcinoma

by Tzu-Ching Chang, Hui-Ting Lee, Siao-Cian Pan, Shih-Han Cho, Chieh Cheng, Liang-Hung Ou, Chia-I Lin, Chen-Sung Lin and Yau-Huei Wei

Int. J. Mol. Sci. 2022, 23(3), 1857; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031857 - 06 Feb 2022

Cited by 4 | Viewed by 2605

Abstract

We used gastric cancer cell line AGS and clinical samples to investigate the roles of mitochondrial DNA (mtDNA) alterations and mitochondrial respiratory dysfunction in gastric adenocarcinoma (GAC). A total of 131 clinical samples, including 17 normal gastric mucosa (N-GM) from overweight patients who had received sleeve gastrectomy and 57 paired non-cancerous gastric mucosae (NC-GM) and GAC from GAC patients who had undergone partial/subtotal/total gastrectomy, were recruited to examine the copy number and D310 sequences of mtDNA. The gastric cancer cell line AGS was used with knockdown (KD) mitochondrial transcription factor A (TFAM) to achieve mitochondrial dysfunction through a decrease of mtDNA copy number. Parental (PT), null-target (NT), and TFAM-KD-(A/B/C) represented the parental, control, and TFAM knocked-down AGS cells, respectively. These cells were used to compare the parameters reflecting mitochondrial biogenesis, glycolysis, and cell migration activity. The median mtDNA copy numbers of 17 N-GM, 57 NC-GM, and 57 GAC were 0.058, 0.055, and 0.045, respectively. The trend of decrease was significant (p = 0.030). In addition, GAC had a lower mean mtDNA copy number of 0.055 as compared with the paired NC-GM of 0.078 (p < 0.001). The mean mtDNA copy number ratio (mtDNA copy number of GAC/mtDNA copy number of paired NC-GM) was 0.891. A total of 35 (61.4%) GAC samples had an mtDNA copy number ratio ≤0.804 (p = 0.017) and 27 (47.4%) harbored a D310 mutation (p = 0.047), and these patients had shorter survival time and poorer prognosis. After effective knockdown of TFAM, TFAM-KD-B/C cells expressed higher levels of hexokinase II (HK-II) and v-akt murine thymoma viral oncogene homolog 1 gene (AKT)-encoded AKT, but lower levels of phosphorylated pyruvate dehydrogenase (p-PDH) than did the NT/PT AGS cells. Except for a higher level of p-PDH, the expression levels of these proteins remained unchanged in TFAM-KD-A, which had a mild knockdown of TFAM. Compared to those of NT, TFAM-KD-C had not only a lower mtDNA copy number (p = 0.050), but also lower oxygen consumption rates (OCR), including basal respiration (OCR_BR), ATP-coupled respiration (OCR_ATP), reserve capacity (OCR_RC), and proton leak (OCR_PL)(all with p = 0.050). In contrast, TFAM-KD-C expressed a higher extracellular acidification rate (ECAR)/OCR_BR ratio (p = 0.050) and a faster wound healing migration at 6, 12, and 18 h, respectively (all with p = 0.050). Beyond a threshold, the decrease in mtDNA copy number, the mtDNA D310 mutation, and mitochondrial dysfunction were involved in the carcinogenesis and progression of GACs. Activation of PDH might be considered as compensation for the mitochondrial dysfunction in response to glucose metabolic reprogramming or to adjust mitochondrial plasticity in GAC. Full article

(This article belongs to the Special Issue Mitochondrial Plasticity in Cancer)

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Review

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24 pages, 892 KiB

Open AccessReview

Tumor Microenvironment and Metabolism: Role of the Mitochondrial Melatonergic Pathway in Determining Intercellular Interactions in a New Dynamic Homeostasis

by George Anderson

Int. J. Mol. Sci. 2023, 24(1), 311; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010311 - 24 Dec 2022

Cited by 10 | Viewed by 2429

Abstract

There is a growing interest in the role of alterations in mitochondrial metabolism in the pathoetiology and pathophysiology of cancers, including within the array of diverse cells that can form a given tumor microenvironment. The ‘exhaustion’ in natural killer cells and CD8+ t cells as well as the tolerogenic nature of dendritic cells in the tumor microenvironment seems determined by variations in mitochondrial function. Recent work has highlighted the important role played by the melatonergic pathway in optimizing mitochondrial function, limiting ROS production, endogenous antioxidants upregulation and consequent impacts of mitochondrial ROS on ROS-dependent microRNAs, thereby impacting on patterned gene expression. Within the tumor microenvironment, the tumor, in a quest for survival, seeks to ‘dominate’ the dynamic intercellular interactions by limiting the capacity of cells to optimally function, via the regulation of their mitochondrial melatonergic pathway. One aspect of this is the tumor’s upregulation of kynurenine and the activation of the aryl hydrocarbon receptor, which acts to metabolize melatonin and increase the N-acetylserotonin/melatonin ratio, with effluxed N-acetylserotonin acting as a brain-derived neurotrophic factor (BDNF) mimic via its activation of the BDNF receptor, TrkB, thereby increasing the survival and proliferation of tumors and cancer stem-like cells. This article highlights how many of the known regulators of cells in the tumor microenvironment can be downstream of the mitochondrial melatonergic pathway regulation. Future research and treatment implications are indicated. Full article

(This article belongs to the Special Issue Mitochondrial Plasticity in Cancer)

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