Mitochondrial Dysfunction: A Novel Potential Driver of Epithelial-to-Mesenchymal Transition in Cancer

Guerra, Flora; Guaragnella, Nicoletta; Arbini, Arnaldo; Bucci, Cecilia; Giannattasio, Sergio; Moro, Loredana

doi:10.3389/fonc.2017.00295

Cited by 99 publications

(89 citation statements)

References 109 publications

(118 reference statements)

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“…Therefore, mitochondrial dysfunction is closely related to many diseases, including cancer. Accumulating evidence indicates that disordered mitochondrial metabolism is associated with tumor invasion and metastasis [91][92][93]. The TCA cycle, one of the main pathways within mitochondria, plays a key role in cell proliferation and provides important intermediates for amino acid, nucleic acid and lipid biosynthesis.…”

Section: The Tca Cycle Is Active During Emtmentioning

confidence: 99%

TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer

Wang

Dijke

Kostidis

et al. 2019

Cell. Mol. Life Sci.

159

120

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Metastasis is the most frequent cause of death in cancer patients. Epithelial-to-mesenchymal transition (EMT) is the process in which cells lose epithelial integrity and become motile, a critical step for cancer cell invasion, drug resistance and immune evasion. The transforming growth factor-β (TGFβ) signaling pathway is a major driver of EMT. Increasing evidence demonstrates that metabolic reprogramming is a hallmark of cancer and extensive metabolic changes are observed during EMT. The aim of this review is to summarize and interconnect recent findings that illustrate how changes in glycolysis, mitochondrial, lipid and choline metabolism coincide and functionally contribute to TGFβ-induced EMT. We describe TGFβ signaling is involved in stimulating both glycolysis and mitochondrial respiration. Interestingly, the subsequent metabolic consequences for the redox state and lipid metabolism in cancer cells are found to be in favor of EMT as well. Combined we illustrate that a better understanding of the mechanistic links between TGFβ signaling, cancer metabolism and EMT holds promising strategies for cancer therapy, some of which are already actively being explored in the clinic.

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Section: The Tca Cycle Is Active During Emtmentioning

confidence: 99%

TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer

Wang

Dijke

Kostidis

et al. 2019

Cell. Mol. Life Sci.

159

120

View full text Add to dashboard Cite

show abstract

“…For instance, enhancing complex I activity has been demonstrated to inhibit tumorigenicity and metastasis of breast cancer cells [15]. More recently, mitochondrial dysfunction has also been associated with a crucial step for tumorigenesis, that is, epithelial-to-mesenchymal transition (EMT), enabling cancer dissemination and metastatic spread [16]. Importantly, mtDNA alterations may also disrupt the inter-genomic crosstalk between nucleus and mitochondrion and is associated with increased oxidative stress, ROS and cytosolic calcium accumulation, reduction of cell ATP levels and an imbalance in the NADH/NAD+ ratio.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA Variations in Tumors: Drivers or Passengers?

Errichiello¹,

Venesio²

2018

Mitochondrial DNA - New Insights

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Mitochondrial DNA alterations, including point mutations, deletions, inversions and copy number variations, have been widely reported in many age-related degenerative diseases and tumors. However, numerous studies investigating their pathogenic role in cancer have provided inconsistent evidence. Furthermore, biological impacts of mitochondrial DNA variants vary tremendously, depending on the proportion of mutant DNA molecules carried by the neoplastic cells (the so-called heteroplasmy). The recent discovery of inter-genomic crosstalk between nucleus and mitochondria has reinforced the role of mitochondrial DNA variants in perturbing this essential signaling pathway and thus indirectly targeting nuclear genes involved in tumorigenic and invasive phenotype. Therefore, mitochondrial dysfunction is currently considered a crucial hallmark of carcinogenesis as well as a promising target for anticancer therapy. This chapter describes the role of different types of mitochondrial DNA alterations by mainly considering the paradigmatic model of colorectal carcinogenesis and, in particular, it revisits the issue of whether mitochondrial mutations are causative cancer drivers or simply genuine passenger events. The advent of high-throughput next-generation sequencing techniques, as well as the development of genetic and pharmaceutical interventions for the treatment of mitochondrial dysfunction in cancer, are also discussed.

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“…Metastasis is usually (but not always) accompanied by the acquisition by tumour cells of traits which decrease cell-cell interactions, and increase motility and resistance to killing by commonly used therapeutics [60]. In recent years, it has become appreciated that mitochondriamediated proliferation and EMT phenotypes are inversely related, though regulated by common pathways [42,44,45,61,62]. For example, analysis of transcriptome data from patient tumour samples has identified that gene sets involved in OXPHOS are commonly changed in tumour tissues compared to normal tissue [52].…”

Section: Discussionmentioning

confidence: 99%

CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism

et al. 2019

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Background Mitochondrial oxidative phosphorylation (OXPHOS) via the respiratory chain is required for the maintenance of tumour cell proliferation and regulation of epithelial to mesenchymal transition (EMT)-related phenotypes through mechanisms that are not fully understood. The essential mitochondrial import protein coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) controls respiratory chain complex activity and oxygen consumption, and regulates the growth of tumours in vivo. In this study, we interrogate the importance of CHCHD4-regulated mitochondrial metabolism for tumour cell proliferation and EMT-related phenotypes, and elucidate key pathways involved. Results Using in silico analyses of 967 tumour cell lines, and tumours from different cancer patient cohorts, we show that CHCHD4 expression positively correlates with OXPHOS and proliferative pathways including the mTORC1 signalling pathway. We show that CHCHD4 expression significantly correlates with the doubling time of a range of tumour cell lines, and that CHCHD4-mediated tumour cell growth and mTORC1 signalling is coupled to respiratory chain complex I (CI) activity. Using global metabolomics analysis, we show that CHCHD4 regulates amino acid metabolism, and that CHCHD4-mediated tumour cell growth is dependent on glutamine. We show that CHCHD4-mediated tumour cell growth is linked to CI-regulated mTORC1 signalling and amino acid metabolism. Finally, we show that CHCHD4 expression in tumours is inversely correlated with EMT-related gene expression, and that increased CHCHD4 expression in tumour cells modulates EMT-related phenotypes. Conclusions CHCHD4 drives tumour cell growth and activates mTORC1 signalling through its control of respiratory chain mediated metabolism and complex I biology, and also regulates EMT-related phenotypes of tumour cells. Electronic supplementary material The online version of this article (10.1186/s40170-019-0200-4) contains supplementary material, which is available to authorized users.

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Mitochondrial Dysfunction: A Novel Potential Driver of Epithelial-to-Mesenchymal Transition in Cancer

Cited by 99 publications

References 109 publications

TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer

TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer

Mitochondrial DNA Variations in Tumors: Drivers or Passengers?

CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism

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