Mitochondrial respiratory defects promote the Warburg effect and cancer progression

Srinivasan, Satish; Guha, Manti; Avadhani, Narayan G.

doi:10.1080/23723556.2015.1085120

Cited by 17 publications

(15 citation statements)

References 10 publications

(15 reference statements)

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“…The role of increased glucose availability on cancer progression is still unclear since the two conditions, increase of insulin and also of glucose levels, are often associated making difficult to dissect the specific role of each one. Cancer cells have an abnormal metabolism and, in contrast to nonmalignant cells, mainly rely on aerobic glycolysis to generate the energy required for their accelerated growth (Warburg effect) [50,51]. To satisfy the increased energy requirement, therefore, they need more glucose ("sugar fuels cancer").…”

Section: Clinical Evidence For a Role Of Insulin And The Insulin Recementioning

confidence: 99%

Insulin, insulin receptors, and cancer

Vigneri

Goldfine

Frittitta

2016

J Endocrinol Invest

179

147

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Insulin is a major regulator of cell metabolism but, in addition, is also a growth factor. Insulin effects in target cells are mediated by the insulin receptor (IR), a transmembrane protein with enzymatic (tyrosine kinase) activity. The insulin receptor, however, is represented by a heterogeneous family of proteins, including two different IR isoforms and also hybrid receptors resulting from the IR hemireceptor combination with a hemireceptor of the cognate IGF-1 receptor. These different receptors may bind insulin and its analogs with different affinity and produce different biologic effects. Since many years, it is known that many cancer cells require insulin for optimal in vitro growth. Recent data indicate that: (1) insulin stimulates growth mainly via its own receptor and not the IGF-1 receptor; (2) in many cancer cells, the IR is overexpressed and the A isoform, which has a predominant mitogenic effect, is more represented than the B isoform. These characteristics provide a selective growth advantage to malignant cells when exposed to insulin. For this reason, all conditions of hyperinsulinemia, both endogenous (prediabetes, metabolic syndrome, obesity, type 2 diabetes before pancreas exhaustion and polycystic ovary syndrome) and exogenous (type 1 diabetes) will increase the risk of cancer. Cancer-related mortality is also increased in patients exposed to hyperinsulinemia but other factors, related to the different diseases, may also contribute. The complexity of the diseases associated with hyperinsulinemia and their therapies does not allow a precise evaluation of the cancer-promoting effect of hyperinsulinemia, but its detrimental effect on cancer incidence and mortality is well documented.

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Section: Clinical Evidence For a Role Of Insulin And The Insulin Recementioning

confidence: 99%

Insulin, insulin receptors, and cancer

Vigneri

Goldfine

Frittitta

2016

J Endocrinol Invest

179

147

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“…mtDNA depletion in cancer cells under drug treatment promotes invasion and metastasis, induces expression of epithelial-to-mesenchymal (EMT) proteins (278) and activates pro-survival and antiapoptotic pathways (279,280). Although the detailed molecular mechanism remains to be determined, several studies have demonstrated that reduced mtDNA content promotes activation of a mitochondria-to-nucleus signaling leading to increased expression of anti-apoptotic genes, including Bcl-2, and activation of pro-survival enzymes, such as Akt (280), that likely play a role in conferring resistance to apoptosis induced by drug treatment. mtDNA depletion in androgen-dependent LNCaP prostate cancer cells resulted in the loss of androgen dependence and increased resistance to paclitaxel (118,119).…”

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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“…The bioenergy is originated from multiple routes, including anaerobic lactate fermentation, aerobic glycolysis, and oxidative phosphorylation (OXPHOS) [9]. According to the theory built-up during the past 80 years as Warburg effect, in cancer cells, shifting bioenergetic metabolism from OXPHOS to aerobic glycolysis is frequently observed especially when dysfunction of respiratory chain occurs in mitochondria [10,11]. However, it has been evident that in addition to the aerobic glycolysis, the OXPHOS also exerts crucial roles in cancer progression [12].…”

Section: Introductionmentioning

confidence: 99%

COX5B-Mediated Bioenergetic Alteration Regulates Tumor Growth and Migration by Modulating AMPK-UHMK1-ERK Cascade in Hepatoma

Chu

Lin

et al. 2020

Cancers

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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.

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Mitochondrial respiratory defects promote the Warburg effect and cancer progression

Cited by 17 publications

References 10 publications

Insulin, insulin receptors, and cancer

Insulin, insulin receptors, and cancer

Metabolic Plasticity in Chemotherapy Resistance

COX5B-Mediated Bioenergetic Alteration Regulates Tumor Growth and Migration by Modulating AMPK-UHMK1-ERK Cascade in Hepatoma

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