Nutrient deprivation-related OXPHOS/glycolysis interconversion via HIF-1α/C-MYC pathway in U251 cells

Liu, Zhong‐Jian; Sun, Yang; Tan, Shirui; Liu, Liang; Hu, Su-qiong; Huo, Hong-yu; Li, Meizhang; Cui, Qinghua; Yu, Min

doi:10.1007/s13277-015-4479-7

Cited by 30 publications

(22 citation statements)

References 35 publications

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“…These results could suggest that the activity of mitochondrial transcription factor A (TFAM) differed between GSCs and differentiated GSCs. Additionally, c‐Myc stimulates mitochondrial transcription factor‐mediated transcription to enhance mitochondrial activity . In the present study, we also found that the expression levels of the TFAM and c‐Myc proteins in GSCs were higher than those detected in isogenic differentiated GSCs.…”

Section: Discussionsupporting

confidence: 71%

“…C). As cytochrome b , COX2 and COX3 are encoded by mitochondrial DNA , we first examined whether the expression levels of mitochondrial transcription factor A (TFAM), a specific transcription factor for mitochondrial genes, and c‐Myc, a transcription activator of TFAM , were different between GSCs and differentiated GSCs. As expected, GSCs expressed TFAM and c‐Myc at high levels compared with differentiated GSCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

et al. 2020

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Glioblastoma multiforme (GBM) is the most malignant primary brain tumour in adults. Since glioma stem cells (GSCs) are associated with therapeutic resistance as well as the initiation and recurrence in GBM, therapies targeting GSCs are considered to be effective for long-term survival in GBM. Several reports suggested that oxidative phosphorylation (OXPHOS) of cancer stem cells is important for their survival; however, the requirement of OXPHOS in GSCs remains unclear. Few effective and safe agents that target GSC mitochondria are available in clinical settings.In this study, we demonstrated that GSCs had high OXPHOS activity compared with isogenic differentiated GSCs and that GSC survival depended on their OXPHOS activity. Remarkably, we showed that complexes III and IV had broad therapeutic windows and that the expression levels of mitochondrial DNA-coded components of complexes III and IV were elevated in GSCs compared with differentiated GSCs. Moreover, our search of the Food and Drug Administration-approved drugs for those targeting GSC mitochondria revealed that verteporfin (Visudyne Ò ), a drug approved for macular degeneration, was a novel GSC-specific cytotoxic compound that reduced OXPHOS activity. Importantly, the cytotoxic effect of verteporfin was specific to GSCs without any toxicity to normal cells, and the IC 50 of approximately 200 nM was ten times less than its maximum blood concentration in humans. Overall, these findings indicated that high mitochondrial OXPHOS of GSCs is a potential GSC-specific vulnerability and that clinically available drugs, such as verteporfin, might become novel GSC-specific cytotoxic agents.

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Section: Discussionsupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

et al. 2020

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“…Consistent with our data, nutrient deprivation-related OXPHOS/glycolysis interconversion has also been observed in a human glioma cell line, although the role of mitochondrial dynamics was not investigated. 26 Our data suggest that mitochondrial dynamic changes may serve as sensors of energy stress and initiators of metabolic reprogramming in HCC cells.…”

Section: Discussionmentioning

confidence: 72%

Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress

et al. 2017

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To date, mechanisms of tumour cell survival under energy stress are not well understood. Cumulative evidence is beginning to reveal that specific mitochondrial morphologies are often associated with energetic states and survival of cells. However, the functional roles of mitochondria in the metabolic adaptation of tumour cells to energy stress remain to be elucidated. In this study, we first investigated the changes in mitochondrial morphology induced by nutrition deprivation in tumour cells, and the underlying molecular mechanism. We then systematically explored glucose metabolism reprogramming by energy stress-induced alteration of mitochondrial morphology and its effect on tumour cell survival. Our results showed that starvation treatment resulted in a dramatic mitochondrial elongation, which was mainly mediated by DRP1 phosphorylation through protein kinase A activation and subsequent suppression of mitochondrial translocation of DRP1. We further observed that tumour cells under an energy stress condition exhibited a clear shift from glycolysis towards oxidative phosphorylation, which was reversed by the recovery of mitochondrial fission induced by forced expression of mutant DRP1. Mechanistically, energy stress-induced mitochondrial elongation facilitated cristae formation and assembly of respiratory complexes to enhance oxidative phosphorylation, which in turn exhibited a feedback inhibitory effect on glycolysis through NAD-dependent SIRT1 activation. In addition, our data indicated that DRP1-mediated mitochondrial elongation under energy stress was essential for tumour cell survival both in vitro and in vivo and predicted poor prognosis of hepatocellular carcinoma patients. Overall, our study demonstrates that remodelling of mitochondrial morphology plays a critical role in tumour cell adaptation to energy stress by reprogramming glucose metabolism.

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“…The present studies show that arsenite differentially regulates HIF-1α and HIF-2α stabilization. In U251 cells, there is interconversion of nutrient deprivation-related OXPHOS and glycolysis via the HIF-1α/C-MYC pathway [50]. In BxPC-3 cells, hypoxia induces overexpression of HIF-1α and enhances expression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A, thus facilitating glycolysis and making tumor cells more tolerant to hypoxic stress [51].…”

Section: Discussionmentioning

confidence: 99%

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

Luo

Liu

Ling

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Accelerated glycolysis, a common process in tumor cells called the Warburg effect, is associated with various biological phenomena. However, the role of glycolysis induced by arsenite, a well-established human carcinogen, is unknown. Long non-coding RNAs (lncRNAs) act as regulators in various cancers, but how lncRNAs regulate glucose metabolism remains largely unexplored. We have found that, in human hepatic epithelial (L-02) cells, arsenite increases lactate production; glucose consumption; and expression of glycolysis-related genes, including HK-2, Eno-1, and Glut-4. In L-02 cells exposed to arsenite, the lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and hypoxia inducible factors (HIFs)-α, the transcriptional regulators of cellular response to hypoxia, are over-expressed. In addition, HIF-1α, not HIF-2α, is involved in arsenite-induced glycolysis, and MALAT1 enhances arsenite-induced glycolysis. Although MALAT1 regulates HIF-α and promotes arsenite-induced glycolysis, MALAT1 promotes glycolysis through HIF-1α, not HIF-2α. Moreover, arsenite-increased MALAT1 enhances the disassociation of Von Hippel-Lindau (VHL) tumor suppressor from HIF-1α, alleviating VHL-mediated ubiquitination of HIF-1α, which causes accumulation of HIF-1α. In sum, these findings indicate that MALAT1, acting through HIF-1α stabilization, is a mediator that enhances glycolysis induced by arsenite. These results provide a link between the induction of lncRNAs and the glycolysis in cells exposed to arsenite, and thus establish a previously unknown mechanism for arsenite-induced hepatotoxicity.

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Nutrient deprivation-related OXPHOS/glycolysis interconversion via HIF-1α/C-MYC pathway in U251 cells

Cited by 30 publications

References 35 publications

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

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