SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1α Destabilization

Finley, Lydia W.S.; Carracedo, Arkaitz; Lee, Jaewon J.; Souza, Amanda; Egia, Ainara; Zhang, Jiangwen; Teruya‐Feldstein, Julie; Moreira, Paula I.; Cardoso, Sandra M.; Clish, Clary B.; Pandolfi, Pier Paolo; Haigis, Marcia C.

doi:10.1016/j.ccr.2011.02.014

Cited by 711 publications

(778 citation statements)

References 50 publications

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“…6e and Supplementary Fig. 11) 44 . Cells cultured in standard medium plus MG132 accumulated hydroxyl-HIF-1α relative to total HIF-1α in response to cell-permeable αKG (Fig.…”

Section: Resultsmentioning

confidence: 98%

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D(R)- or L(S)- enantiomer, each of which inhibits alpha-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via ‘promiscuous’ reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.

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“…6e and Supplementary Fig. 11) 44 . Cells cultured in standard medium plus MG132 accumulated hydroxyl-HIF-1α relative to total HIF-1α in response to cell-permeable αKG (Fig.…”

Section: Resultsmentioning

confidence: 98%

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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“…This modification by 4-HNE can inhibit SIRT3 deacetylase activity (Fritz et al, 2011). Moreover, SIRT3 was reported to destabilize HIF-1α protein and inhibit its activity (Finley et al, 2011). Thus we suppose that the regulation of cell growth, invasion and VEGF expression by 4-HNE to the breast cancer cells may be the results of 4-HNE induced SIRT3 inhibition and stabilization of HIF-1α protein.…”

Section: -Hydroxynonenal Promotes the Growth And Invasion Of Breast mentioning

confidence: 99%

“…*p<0.02, **p<0.004 compared with the control group (C) VEGF levels in the culture medium determined by ELISA HIF-1α is detectable from isolated nuclei under normoxic conditions. This provides the possibility to study HIF-1α protein under normoxic conditions (Finley et al, 2011).To test this idea we first investigated whether 4-HNE affects the levels of HIF-1α protein under normoxic conditions. A significant increase of HIF-1α protein was found in breast cancer cells after the treatment with 4-HNE ( Figure 3A).…”

Section: -Hydroxynonenal Promotes the Growth And Invasion Of Breast mentioning

confidence: 99%

“…Under the normoxic conditions, HIF-1α is degraded via the ubiquitin-proteasome pathway by binding of the von Hippel-Lindau tumor suppressor protein (pVHL) to the oxygen-dependent degradation domain (ODD) (Maxwell et al, 1999). HIF-1α protein is rapidly degraded and difficult to detect from cell lysates under normoxic conditions (Groulx and Lee, 2002) however, various factors can activate HIF-1α even under normoxic conditions and HIF-1α is detectable from isolated nuclei under normoxic conditions (Finley et al, 2011). This provides the possibility to study HIF-1α protein under normoxic conditions.…”

Section: Introductionmentioning

confidence: 99%

“…The stability of HIF-1α was regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, sumoylation and phosphorylation (Ke and Costa, 2006;Ulrich, 2007;van Hagen et al, 2010). Sirtuin-3 (SIRT3), a major mitochondria NAD+-dependent deacetylase, was reported to destabilize HIF-1α (Finley et al, 2011;Chen et al, 2014). Under the normoxic conditions, HIF-1α is degraded via the ubiquitin-proteasome pathway by binding of the von Hippel-Lindau tumor suppressor protein (pVHL) to the oxygen-dependent degradation domain (ODD) (Maxwell et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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4-Hydroxynonenal Promotes Growth and Angiogenesis of Breast Cancer Cells through HIF-1α Stabilization

Li¹,

Tian²,

Shi³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Abstract4-Hydroxynonenal (4-HNE) is a stable end product of lipid peroxidation, which has been shown to play an important role in cell signal transduction, while increasing cell growth and differentiation. 4-HNE could inhibit phosphatase and tensin homolog (PTEN) activity in hepatocytes and increased levels have been found in human invasive breast cancer. Here we report that 4-HNE increased the cell growth of breast cancer cells as revealed by colony formation assay. Moreover, vascular endothelial growth factor (VEGF) expression was elevated, while protein levels of hypoxia inducible factor 1 alpha (HIF-1α) were up-regulated. Sirtuin-3 (SIRT3), a major mitochondria NAD+-dependent deacetylase, is reported to destabilize HIF-1α. Here, 4-HNE could inhibit the deacetylase activity of SIRT3 by thiol-specific modification. We further demonstrated that the regulation by 4-HNE of levels of HIF-1α and VEGF depends on SIRT3. Consistent with this, 4-HNE could not increase the cell growth in SIRT3 knockdown breast cancer cells. Additionally, 4-HNE promoted angiogenesis and invasion of breast cancer cells in a SIRT3-dependent manner. In conclusion, we propose that 4-HNE promotes growth, invasion and angiogenesis of breast cancer cells through the SIRT3-HIF-1α-VEGF axis.

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Metabolic reprogramming: a bridge between aging and tumorigenesis

2022

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Aging is the most robust risk factor for cancer development, with more than 60% of cancers occurring in those aged 60 and above. However, how aging and tumorigenesis are intertwined is poorly understood and a matter of significant debate. Metabolic changes are hallmarks of both aging and tumorigenesis. The deleterious consequences of aging include dysfunctional cellular processes, the build-up of metabolic byproducts and waste molecules in circulation and within tissues, and stiffer connective tissues that impede blood flow and oxygenation. Collectively, these age-driven changes lead to metabolic reprogramming in different cell types of a given tissue that significantly affects their cellular functions. Here, we put forward the idea that metabolic changes that happen during aging help create a favorable environment for tumorigenesis. We review parallels in metabolic changes that happen during aging and how these changes function both as adaptive mechanisms that enable the development of malignant phenotypes in a cell-autonomous manner and as mechanisms that suppress immune surveillance, collectively creating the perfect environment for cancers to thrive. Hence, antiaging therapeutic strategies that target the metabolic reprogramming that occurs as we age might provide new opportunities to prevent cancer initiation and/or improve responses to standard-of-care anticancer therapies.

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SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1α Destabilization

Cited by 711 publications

References 50 publications

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

4-Hydroxynonenal Promotes Growth and Angiogenesis of Breast Cancer Cells through HIF-1α Stabilization

Metabolic reprogramming: a bridge between aging and tumorigenesis

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