HIF-1-Mediated Suppression of Acyl-CoA Dehydrogenases and Fatty Acid Oxidation Is Critical for Cancer Progression

Huang, De; Li, Tingting; Li, Xinghua; Zhang, Long; Sun, Linchong; He, Xiaoping; Zhong, Xiuying; Jia, Dongya; Song, Libing; Semenza, Gregg L.; Gao, Ping; Zhang, Huafeng

doi:10.1016/j.celrep.2014.08.028

Cited by 268 publications

(233 citation statements)

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“…We have uncovered cMyc-mediated activation of serine synthesis pathway when glucose or glutamine is deprived [18] and HIF-1-mediated suppression of fatty acid β-oxidation when oxygen is scarce [16]. Further screening for changes of lipid metabolism-related genes led us to a surprising observation that a major enzyme for ketolysis, OXCT1, is dramatically induced in nutrition-deprived HCC cells.…”

Section: Introductionmentioning

confidence: 99%

“…Our recent work showed that fatty acid β-oxidation in cancer cells is inhibited to ease oxidative stress and to activate proliferative signaling under hypoxic microenvironment [16]. We further investigated lipid metabolic changes under specific nutrition-limiting conditions.…”

Section: Ketolysis Is Re-activated In Nutrition-starved Hcc Cells To mentioning

confidence: 99%

“…Recently, we investigated the metabolic adaptation of human hepatocellular carcinoma (HCC) cells under various stress conditions [16][17][18]. We have uncovered cMyc-mediated activation of serine synthesis pathway when glucose or glutamine is deprived [18] and HIF-1-mediated suppression of fatty acid β-oxidation when oxygen is scarce [16].…”

Section: Introductionmentioning

confidence: 99%

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Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

et al. 2016

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Cancer cells are known for their capacity to rewire metabolic pathways to support survival and proliferation under various stress conditions. Ketone bodies, though produced in the liver, are not consumed in normal adult liver cells. We find here that ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma (HCC) cells under nutrition deprivation conditions. Mechanistically, 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting ketolytic enzyme whose expression is suppressed in normal adult liver tissues, is re-induced by serum starvation-triggered mTORC2-AKT-SP1 signaling in HCC cells. Moreover, we observe that enhanced ketolysis in HCC is critical for repression of AMPK activation and protects HCC cells from excessive autophagy, thereby enhancing tumor growth. Importantly, analysis of clinical HCC samples reveals that increased OXCT1 expression predicts higher patient mortality. Taken together, we uncover here a novel metabolic adaptation by which nutrition-deprived HCC cells employ ketone bodies for energy supply and cancer progression.

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Section: Introductionmentioning

confidence: 99%

Section: Ketolysis Is Re-activated In Nutrition-starved Hcc Cells To mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

et al. 2016

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“…The hypoxic TME triggers, also through oxidative stress −as shown in ovarian and prostate cancers [117][118][119], the tumor production of angiogenetic factors such as vascular-endothelial-growth-factor (VEGF), by upregulating hypoxia-inducible factor-1α (HIF-1α) [120]. Interestingly, HIF-1α is able to limit ROS accumulation in tumor cells, thus promoting cancer progression at later stages, by limiting the production of acetyl-CoA (the key molecule entering the TCA cycle) from glycolysis [121] and fattyacid oxidation [122]. Indeed, the activity of TCA cycle enzymes and ETC complexes under hypoxic conditions may lead to uncontrolled ROS accumulation, which is harmful to cancer cells [123].…”

Section: Mitochondrial Dynamics and Ros Production In Cancermentioning

confidence: 99%

The mitochondrial dynamics in cancer and immune-surveillance

Simula

Nazio

Campello

2017

Seminars in Cancer Biology

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A B S T R A C TMitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system. By this review, we overview how mitochondrial dynamics can affect various processes during cancer development, acting directly on tumor cells or indirectly on cells responsible for tumor aggression and defence.

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“…HIF1α is reportedly involved in PD in GC, colorectal cancer, and pancreatic cancer [35,37] . HIF1α is induced by hypoxia and functions as a master regulator of cellular and systemic homeostatic responses to hypoxia by activating the transcription of many genes, including those involved in glucose metabolism and other adaptations to hypoxia [38][39][40] . Interestingly, HIF1α induces EMT by activating the transcription of genes in the LOX family [41] .…”

Section: Cell Survival In the Microenvironment Of The Peritoneal Cavitymentioning

confidence: 99%

Molecular mechanism of peritoneal dissemination in gastric cancer

Hu¹,

Ito²,

Yanagihara³

et al. 2018

JCMT

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Peritoneal dissemination (PD) is the most common cause of metastasis in gastric cancer (GC). Because there are no standard treatments for PD, it is associated with a poor prognosis. Although clinicians have performed intraperitoneal chemotherapy for GC with PD, the outcome remains unsatisfactory. Therefore, the development of novel treatments and diagnostic tools for PD is expected to improve the prognosis of GC patients with PD. Notably, it is essential to elucidate the molecular mechanisms involved in the development of PD in GC. In this review, the molecular mechanisms of PD (three steps: detachment from the primary tumor, adaptation to the microenvironment of the peritoneal cavity, and attachment to peritoneal mesothelial cells) and new topics in GC are highlighted.

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HIF-1-Mediated Suppression of Acyl-CoA Dehydrogenases and Fatty Acid Oxidation Is Critical for Cancer Progression

Cited by 268 publications

References 31 publications

Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

The mitochondrial dynamics in cancer and immune-surveillance

Molecular mechanism of peritoneal dissemination in gastric cancer

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