Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses

Kurelac, Ivana; Iommarini, Luisa; Vatrinet, Renaud; Amato, Laura Benedetta; Luise, Monica De; Leone, Giulia; Girolimetti, Giulia; Ganesh, Nikkitha Umesh; Bridgeman, Victoria L.; Ombrato, Luigi; Columbaro, Marta; Ragazzi, Moira; Gibellini, Lara; Sollazzo, Manuela; Feichtinger, René G.; Vidali, Silvia; Baldassarre, Maurizio; Foriel, Sarah; Vidone, Michele; Cossarizza, Andrea; Grifoni, Daniela; Kofler, Barbara; Malanchi, Ilaria; Porcelli, Anna Maria; Gasparre, Giuseppe

doi:10.1038/s41467-019-08839-1

Cited by 47 publications

(84 citation statements)

References 57 publications

(71 reference statements)

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“…In our study, mtDNA variation and depletion indeed showed HIF-1α destabilization. This was confirmed in a recent proof of concept study in 2 different tumor backgrounds (HCT116 and 143B) having a nuclear-encoded NDUFS3 knock-out, where HIF-1α stabilization was abolished, but that tumors were able to re-adapt to the hypoxia response (50). These adaptations to hypoxia are supported by the observed increase in HIF-2 expression in the cybrid mutant xenografts, which also has been evidenced from our recently published work (21).…”

Section: Discussionsupporting

confidence: 81%

Mitochondrial Dysfunction Inhibits Hypoxia-Induced HIF-1α Stabilization and Expression of Its Downstream Targets

et al. 2020

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mtDNA variations often result in bioenergetic dysfunction inducing a metabolic switch toward glycolysis resulting in an unbalanced pH homeostasis. In hypoxic cells, expression of the tumor-associated carbonic anhydrase IX (CAIX) is enhanced to maintain cellular pH homeostasis. We hypothesized that cells with a dysfunctional oxidative phosphorylation machinery display elevated CAIX expression levels. Increased glycolysis was observed for cytoplasmic 143B mutant hybrid (m.3243A>G, >94.5%) cells (p < 0.05) and 143B mitochondrial DNA (mtDNA) depleted cells (p < 0.05). Upon hypoxia (0.2%, 16 h), genetic or pharmacological oxidative phosphorylation (OXPHOS) inhibition resulted in decreased CAIX (p < 0.05), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1α) expression levels. Reactive oxygen species (ROS) and prolyl-hydroxylase 2 (PHD2) levels could not explain these observations. In vivo, tumor take (>500 mm 3) took longer for mutant hybrid xenografts, but growth rates were comparable with control tumors upon establishment. Previously, it has been shown that HIF-1α is responsible for tumor establishment. In agreement, we found that HIF-1α expression levels and the pimonidazole-positive hypoxic fraction were reduced for the mutant hybrid xenografts. Our results demonstrate that OXPHOS dysfunction leads to a decreased HIF-1α stabilization and subsequently to a reduced expression of its downstream targets and hypoxic fraction in vivo. In contrast, hypoxia-inducible factor 2-alpha (HIF-2α) expression levels in these xenografts were enhanced. Inhibition of mitochondrial function is therefore an interesting approach to increase therapeutic efficacy in hypoxic tumors.

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Section: Discussionsupporting

confidence: 81%

Mitochondrial Dysfunction Inhibits Hypoxia-Induced HIF-1α Stabilization and Expression of Its Downstream Targets

et al. 2020

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“…The ability of metformin to inhibit mitochondrial respiratory-chain complex 1 means the drug has potential use for tumorigenesis inhibition 12 . A recent 2019 study reported the benefit of using metformin as an adjuvant therapy in patients with cancer 246 . Many clinical trials have reported encouraging results in protecting patients with T2DM from cancer 245 but the protective effect of metformin remains to be validated in individuals without T2DM.…”

Section: Box 3: Metformin Therapeutic Repurposingmentioning

confidence: 99%

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

2019

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Despite its position as the first-line treatment for type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. Furthermore, the discovery that metformin inhibits the mitochondrial respiratory-chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the center of its mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations of cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase-1 (FBP1) and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3phosphate dehydrogenase (mG3PDH) are proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissueresident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide-1 (GLP-1) and intestinal bile acid pool and alterations in gut microbiota composition. 3 Key points • Metformin is the first-line drug for treatment of type 2 diabetes mellitus, with an excellent safety profile, high efficacy on glycaemic control and clear but incompletely understood cardioprotective benefits. • The pleiotropic properties of metformin suggest that the drug acts on multiple tissues through various underlying mechanisms rather than on a single organ via an unifying mode of action. • The mitochondrial respiratory-chain complex 1 is a key cellular target of metformin and its mild and transient inhibition is involved in the AMPK-independent regulation of hepatic gluconeogenesis by triggering alterations in the cellular energy charge and redox state. • Metformin might contribute to improvements in obesity-associated metainflammation and tissue-specific insulin sensitivity through direct and indirect effects on various resident immune cells in metabolic organs. • The gastrointestinal tract has an important role in the action of metformin, which modulates bile acid recirculation and enhances the secretion of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP1). • The gut microbiota represents a novel target in the mechanisms of metformin action and is involved in both the therapeutic and adverse effects of the drug.

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“…On the other side, non-disassembling mild mtDNA CI mutations could stimulate tumor proliferation and metastases. The oncojanus function of CI subunits was described for both mitochondrial and nuclear encoded CI subunits (272,273). CI disruption inhibits OxPhos, promote NADH accumulation, inhibition of α-ketoglutarate dehydrogenase and increase the α-Ketoglutarate (KG)/succinate ratio.…”

Section: Targeting Mitochondria Metabolismmentioning

confidence: 99%

“…The α-Ketoglutarate (KG)/succinate imbalance activates prolylhydroxylases (PDH) enzymes responsible for the hydroxylation and degradation of HIF-1α even in hypoxic conditions (271,274). Of note, genetical and pharmacological targeting of CI activity in osteosarcoma and colorectal cancer cell models successfully converted a carcinoma into a benign low-proliferating and noninvasive oncocytic tumor (273).…”

Section: Targeting Mitochondria Metabolismmentioning

confidence: 99%

Metabolic Plasticity in Chemotherapy Resistance

et al. 2020

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Resistance of cancer cells to chemotherapy is the first cause of cancer-associated death. Thus, new strategies to deal with the evasion of drug response and to improve clinical outcomes are needed. Genetic and epigenetic mechanisms associated with uncontrolled cell growth result in metabolism reprogramming. Cancer cells enhance anabolic pathways and acquire the ability to use different carbon sources besides glucose. An oxygen and nutrient-poor tumor microenvironment determines metabolic interactions among normal cells, cancer cells and the immune system giving rise to metabolically heterogeneous tumors which will partially respond to metabolic therapy. Here we go into the best-known cancer metabolic profiles and discuss several studies that reported tumors sensitization to chemotherapy by modulating metabolic pathways. Uncovering metabolic dependencies across different chemotherapy treatments could help to rationalize the use of metabolic modulators to overcome therapy resistance.

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Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses

Cited by 47 publications

References 57 publications

Mitochondrial Dysfunction Inhibits Hypoxia-Induced HIF-1α Stabilization and Expression of Its Downstream Targets

Mitochondrial Dysfunction Inhibits Hypoxia-Induced HIF-1α Stabilization and Expression of Its Downstream Targets

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

Metabolic Plasticity in Chemotherapy Resistance

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