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Cancers
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Mitochondria Metabolism and Cancer Therapy
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Mitochondria Metabolism and Cancer Therapy

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

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 26702

Special Issue Editors

Prof. Dr. Barbara Kofler

E-Mail Website
Guest Editor
Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, 5020 Salzburg, Austria
Interests: metabolism; mitochondria; cancer; neuroblastoma; dietary intervention
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Marie Arsenian-Henriksson

E-Mail Website
Guest Editor
Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology, Nobelsväg 16, 17177 Stockholm, Sweden
Interests: pediatric cancer; cancer metabolism; mitochondria; oxidative phosphorylation; lipid metabolism; targeted therapy

Special Issue Information

Dear Colleagues,

Cancer is one of the most devastating and intractable diseases. Alterations of cellular metabolism, in particular of glycolysis and mitochondrial metabolism, are recognized hallmarks of most types of cancer. Adaptation of the cellular metabolism in cancer provides the necessary energy and building blocks for macromolecules, which are essential for cell proliferation. Mitochondria also regulate redox and calcium homeostasis, participate in transcriptional regulation, and govern cell death. Therefore, therapies targeting diverse mitochondrial metabolic functions have emerged as a novel potent option to enhance the efficacy of established anti-cancer treatments such as radio- and chemotherapy as well as immunotherapy. This Special Issue of Cancers will include the latest research on mitochondrial metabolism in cancer and the cancer microenvironment with a focus on the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.

This Special Issue welcomes both original papers and review articles addressing one or several of the above-mentioned issues, or of the topics mentioned in the keywords listed below.

 

Prof. Dr. Barbara Kofler
Prof. Dr. Marie Arsenian-Henriksson
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

  • Overview of mitochondrial metabolism in cancer
  • Genetic alterations and mitochondrial function
  • Metabolic flexibility
  • Metabolic flux and metabolomics
  • Microenvironment
  • Diagnosis and prognosis
  • Cancer therapy and resistance
  • Repurposing of drugs to target mitochondrial metabolism

Published Papers (6 papers)

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Research

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14 pages, 2961 KiB  
Article
Inhibition of Heme Export and/or Heme Synthesis Potentiates Metformin Anti-Proliferative Effect on Cancer Cell Lines
by Anna Lucia Allocco, Francesca Bertino, Sara Petrillo, Deborah Chiabrando, Chiara Riganti, Alberto Bardelli, Fiorella Altruda, Veronica Fiorito and Emanuela Tolosano
Cancers 2022, 14(5), 1230; https://doi.org/10.3390/cancers14051230 - 27 Feb 2022
Cited by 7 | Viewed by 2289
Abstract
Cancer is one of the leading causes of mortality worldwide. Beyond standard therapeutic options, whose effectiveness is often reduced by drug resistance, repurposing of the antidiabetic drug metformin appears promising. Heme metabolism plays a pivotal role in the control of metabolic adaptations that [...] Read more.
Cancer is one of the leading causes of mortality worldwide. Beyond standard therapeutic options, whose effectiveness is often reduced by drug resistance, repurposing of the antidiabetic drug metformin appears promising. Heme metabolism plays a pivotal role in the control of metabolic adaptations that sustain cancer cell proliferation. Recently, we demonstrated the existence of a functional axis between the heme synthetic enzyme ALAS1 and the heme exporter FLVCR1a exploited by cancer cells to down-modulate oxidative metabolism. In colorectal cancer cell lines, the inhibition of heme synthesis-export system was associated with reduced proliferation and survival. Here, we aim to assess whether the inhibition of the heme synthesis-export system affects the sensitivity of colorectal cancer cells to metformin. Our data demonstrate that the inhibition of this system, either by blocking heme efflux with a FLVCR1a specific shRNA or by inhibiting heme synthesis with 5-aminolevulinic acid, improves metformin anti-proliferative effect on colorectal cancer cell lines. In addition, we demonstrated that the same effect can be obtained in other kinds of cancer cell lines. Our study provides an in vitro proof of concept of the possibility to target heme metabolism in association with metformin to counteract cancer cell growth. Full article
(This article belongs to the Special Issue Mitochondria Metabolism and Cancer Therapy)
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14 pages, 4164 KiB  
Article
Receptor-Mediated Mitophagy Rescues Cancer Cells under Hypoxic Conditions
by Alibek Abdrakhmanov, Maria A. Yapryntseva, Vitaliy O. Kaminskyy, Boris Zhivotovsky and Vladimir Gogvadze
Cancers 2021, 13(16), 4027; https://doi.org/10.3390/cancers13164027 - 10 Aug 2021
Cited by 11 | Viewed by 2731
Abstract
Targeting mitochondria with thenoyltrifluoroacetone (TTFA), an inhibitor of Complex II in the respiratory chain, stimulated cisplatin-induced apoptosis in various cell lines in normoxia but not in hypoxia. This can be explained by the elimination of mitochondria involved in triggering apoptotic cell death by [...] Read more.
Targeting mitochondria with thenoyltrifluoroacetone (TTFA), an inhibitor of Complex II in the respiratory chain, stimulated cisplatin-induced apoptosis in various cell lines in normoxia but not in hypoxia. This can be explained by the elimination of mitochondria involved in triggering apoptotic cell death by mitophagy, either Parkin-dependent or receptor-mediated. Treatment with TTFA alone or in combination with cisplatin did not cause accumulation of PINK1, meaning that under hypoxic conditions cells survive through activation of a receptor-mediated pathway. Hypoxia triggers the accumulation of BNIP3 and BNIP3L (also known as NIX), key participants in receptor-mediated mitophagy. Under hypoxic conditions, stimulation of autophagy, as assessed by the accumulation of lipidated form of LC3 (LC3II), was observed. To exclude the contribution of canonical macroautophagy in LC3II accumulation, experiments were performed using U1810 cells lacking ATG13, a key enzyme of macroautophagy. Despite the absence of ATG13, hypoxia-mediated accumulation of LC3II was not affected, underlying the importance of the receptor-mediated pathway. In order to prove the protective role of BNIP3 against cisplatin-induced apoptosis, BNIP3-deficient A549 cells were used. Surprisingly, a BNIP3 knockout did not abolish hypoxia-induced protection; however, in cells lacking BNIP3, a compensatory upregulation of BNIP3L was detected. Thus, in the absence of BNIP3, mitophagy could be maintained by BNIP3L and lead to cell death suppression due to the elimination of proapoptotic mitochondria. When both BNIP3 and BNIP3L were knocked out, the inhibitory effect of hypoxia on apoptosis was diminished, although not abolished completely. Undoubtedly, receptor-mediated mitophagy is likely to be one of the mechanisms responsible for cell death suppression under hypoxic conditions. Full article
(This article belongs to the Special Issue Mitochondria Metabolism and Cancer Therapy)
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27 pages, 6222 KiB  
Article
Metformin Is a Pyridoxal-5′-phosphate (PLP)-Competitive Inhibitor of SHMT2
by Angela Tramonti, Elisabet Cuyàs, José Antonio Encinar, Matthias Pietzke, Alessio Paone, Sara Verdura, Aina Arbusà, Begoña Martin-Castillo, Giorgio Giardina, Jorge Joven, Alexei Vazquez, Roberto Contestabile, Francesca Cutruzzolà and Javier A. Menendez
Cancers 2021, 13(16), 4009; https://doi.org/10.3390/cancers13164009 - 9 Aug 2021
Cited by 13 | Viewed by 5093
Abstract
The anticancer actions of the biguanide metformin involve the functioning of the serine/glycine one-carbon metabolic network. We report that metformin directly and specifically targets the enzymatic activity of mitochondrial serine hydroxymethyltransferase (SHMT2). In vitro competitive binding assays with human recombinant SHMT1 and SHMT2 [...] Read more.
The anticancer actions of the biguanide metformin involve the functioning of the serine/glycine one-carbon metabolic network. We report that metformin directly and specifically targets the enzymatic activity of mitochondrial serine hydroxymethyltransferase (SHMT2). In vitro competitive binding assays with human recombinant SHMT1 and SHMT2 isoforms revealed that metformin preferentially inhibits SHMT2 activity by a non-catalytic mechanism. Computational docking coupled with molecular dynamics simulation predicted that metformin could occupy the cofactor pyridoxal-5′-phosphate (PLP) cavity and destabilize the formation of catalytically active SHMT2 oligomers. Differential scanning fluorimetry-based biophysical screening confirmed that metformin diminishes the capacity of PLP to promote the conversion of SHMT2 from an inactive, open state to a highly ordered, catalytically competent closed state. CRISPR/Cas9-based disruption of SHMT2, but not of SHMT1, prevented metformin from inhibiting total SHMT activity in cancer cell lines. Isotope tracing studies in SHMT1 knock-out cells confirmed that metformin decreased the SHMT2-channeled serine-to-formate flux and restricted the formate utilization in thymidylate synthesis upon overexpression of the metformin-unresponsive yeast equivalent of mitochondrial complex I (mCI). While maintaining its capacity to inhibit mitochondrial oxidative phosphorylation, metformin lost its cytotoxic and antiproliferative activity in SHMT2-null cancer cells unable to produce energy-rich NADH or FADH2 molecules from tricarboxylic acid cycle (TCA) metabolites. As currently available SHMT2 inhibitors have not yet reached the clinic, our current data establishing the structural and mechanistic bases of metformin as a small-molecule, PLP-competitive inhibitor of the SHMT2 activating oligomerization should benefit future discovery of biguanide skeleton-based novel SHMT2 inhibitors in cancer prevention and treatment. Full article
(This article belongs to the Special Issue Mitochondria Metabolism and Cancer Therapy)
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23 pages, 3811 KiB  
Article
Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells
by Ana Carolina B. Sant’Anna-Silva, Juan A. Perez-Valencia, Marco Sciacovelli, Claude Lalou, Saharnaz Sarlak, Laura Tronci, Efterpi Nikitopoulou, Andras T. Meszaros, Christian Frezza, Rodrigue Rossignol, Erich Gnaiger and Helmut Klocker
Cancers 2021, 13(7), 1727; https://doi.org/10.3390/cancers13071727 - 6 Apr 2021
Cited by 13 | Viewed by 3810
Abstract
Tumor cells display metabolic alterations when compared to non-transformed cells. These characteristics are crucial for tumor development, maintenance and survival providing energy supplies and molecular precursors. Anaplerosis is the property of replenishing the TCA cycle, the hub of carbon metabolism, participating in the [...] Read more.
Tumor cells display metabolic alterations when compared to non-transformed cells. These characteristics are crucial for tumor development, maintenance and survival providing energy supplies and molecular precursors. Anaplerosis is the property of replenishing the TCA cycle, the hub of carbon metabolism, participating in the biosynthesis of precursors for building blocks or signaling molecules. In advanced prostate cancer, an upshift of succinate-driven oxidative phosphorylation via mitochondrial Complex II was reported. Here, using untargeted metabolomics, we found succinate accumulation mainly in malignant cells and an anaplerotic effect contributing to biosynthesis, amino acid, and carbon metabolism. Succinate also stimulated oxygen consumption. Malignant prostate cells displayed higher mitochondrial affinity for succinate when compared to non-malignant prostate cells and the succinate-driven accumulation of metabolites induced expression of mitochondrial complex subunits and their activities. Moreover, extracellular succinate stimulated migration, invasion, and colony formation. Several enzymes linked to accumulated metabolites in the malignant cells were found upregulated in tumor tissue datasets, particularly NME1 and SHMT2 mRNA expression. High expression of the two genes was associated with shorter disease-free survival in prostate cancer cohorts. Moreover, in-vitro expression of both genes was enhanced in prostate cancer cells upon succinate stimulation. In conclusion, the data indicate that uptake of succinate from the tumor environment has an anaplerotic effect that enhances the malignant potential of prostate cancer cells. Full article
(This article belongs to the Special Issue Mitochondria Metabolism and Cancer Therapy)
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23 pages, 7031 KiB  
Article
COX5B-Mediated Bioenergetic Alteration Regulates Tumor Growth and Migration by Modulating AMPK-UHMK1-ERK Cascade in Hepatoma
by Yu-De Chu, Wey-Ran Lin, Yang-Hsiang Lin, Wen-Hsin Kuo, Chin-Ju Tseng, Siew-Na Lim, Yen-Lin Huang, Shih-Chiang Huang, Ting-Jung Wu, Kwang-Huei Lin and Chau-Ting Yeh
Cancers 2020, 12(6), 1646; https://doi.org/10.3390/cancers12061646 - 22 Jun 2020
Cited by 20 | Viewed by 3040
Abstract
The oxidative phosphorylation machinery in mitochondria, which generates the main bioenergy pool in cells, includes four enzyme complexes for electron transport and ATP synthase. Among them, the cytochrome c oxidase (COX), which constitutes the fourth complex, has been suggested as the major regulatory [...] Read more.
The oxidative phosphorylation machinery in mitochondria, which generates the main bioenergy pool in cells, includes four enzyme complexes for electron transport and ATP synthase. Among them, the cytochrome c oxidase (COX), which constitutes the fourth complex, has been suggested as the major regulatory site. Recently, abnormalities in COX were linked to tumor progression in several cancers. However, it remains unclear whether COX and its subunits play a role in tumor progression of hepatoma. To search for the key regulatory factor(s) in COX for hepatoma development, in silico analysis using public transcriptomic database followed by validation for postoperative outcome associations using independent in-house patient cohorts was performed. In which, COX5B was highly expressed in hepatoma and associated with unfavorable postoperative prognosis. In addressing the role of COX5B in hepatoma, the loss- and gain-of-function experiments for COX5B were conducted. Consequently, COX5B expression was associated with increased hepatoma cell proliferation, migration and xenograft growth. Downstream effectors searched by cDNA microarray analysis identified UHMK1, an oncogenic protein, which manifested a positively correlated expression level of COX5B. The COX5B-mediated regulatory event on UHMK1 expression was subsequently demonstrated as bioenergetic alteration-dependent activation of AMPK in hepatoma cells. Phosphoproteomic analysis uncovered activation of ERK- and stathmin-mediated pathways downstream of UHMK1. Finally, comprehensive phenotypic assays supported the impacts of COX5B-UHMK1-ERK axis on hepatoma cell growth and migration. Full article
(This article belongs to the Special Issue Mitochondria Metabolism and Cancer Therapy)
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24 pages, 1847 KiB  
Review
Succinate Dehydrogenase and Ribonucleic Acid Networks in Cancer and Other Diseases
by Cerena Moreno, Ruben Mercado Santos, Robert Burns and Wen Cai Zhang
Cancers 2020, 12(11), 3237; https://doi.org/10.3390/cancers12113237 - 3 Nov 2020
Cited by 21 | Viewed by 8541
Abstract
Succinate dehydrogenase (SDH) complex connects both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) in the mitochondria. However, SDH mutation or dysfunction-induced succinate accumulation results in multiple cancers and non-cancer diseases. The mechanistic studies show that succinate activates hypoxia response [...] Read more.
Succinate dehydrogenase (SDH) complex connects both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) in the mitochondria. However, SDH mutation or dysfunction-induced succinate accumulation results in multiple cancers and non-cancer diseases. The mechanistic studies show that succinate activates hypoxia response and other signal pathways via binding to 2-oxoglutarate-dependent oxygenases and succinate receptors. Recently, the increasing knowledge of ribonucleic acid (RNA) networks, including non-coding RNAs, RNA editors, and RNA modifiers has expanded our understanding of the interplay between SDH and RNA networks in cancer and other diseases. Here, we summarize recent discoveries in the RNA networks and their connections to SDH. Additionally, we discuss current therapeutics targeting SDH in both pre-clinical and clinical trials. Thus, we propose a new model of SDH–RNA network interaction and bring promising RNA therapeutics against SDH-relevant cancer and other diseases. Full article
(This article belongs to the Special Issue Mitochondria Metabolism and Cancer Therapy)
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