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Hif1α-Dependent Uncoupling Of Glycolysis Suppresses Tumor Cell Proliferation

ABSTRACT: Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. Paradoxically, it remains unknown why lower glycolysis is compromised in human clear cell renal cell carcinomas (ccRCC), in which HIF1α acts a tumor suppressor by inhibiting cell autonomous proliferation. Here we found that unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio.

INSTRUMENT(S): Gas Chromatography MS - positive, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS8901 | MetaboLights | 2024-03-15

REPOSITORIES: MetaboLights

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HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation.

Urrutia Andrés A AA Mesa-Ciller Claudia C Guajardo-Grence Andrea A Alkan H Furkan HF Soro-Arnáiz Inés I Vandekeere Anke A Ferreira Campos Ana Margarida AM Igelmann Sebastian S Fernández-Arroyo Lucía L Rinaldi Gianmarco G Lorendeau Doriane D De Bock Katrien K Fendt Sarah-Maria SM Aragonés Julián J

Cell reports 20240411 4

Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited ...[more]

PMID: 38607920

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Project description:Previous findings have demonstrated that the NADH/NAD+ ratio has a strong impact on the glycolytic flux in C. glutamicum under anaerobic conditions in the absence of external electron acceptors. During an attempt to rewire anaerobic metabolism to achieve high yield formation of ethanol, we inactivated the malate dehydrogenase and lactate dehydrogenase in a C. glutamicum strain expressing pyruvate decarboxylase and alcohol dehydrogenase, to eliminate formation of the by-products succinate and lactate, respectively. This modification increased the yield of ethanol but had a negative effect on glycolysis, which we found to correlate with an elevated NADH/NAD+ ratio. The pyruvate dehydrogenase (PDH) of C. glutamicum is active under anaerobic conditions, and can potentially exacerbate the negative effect on glycolysis, due to NADH formation. To reduce PDH activity under anaerobic conditions, we decided to replace the gene encoding the E3 subunit of PDH with its Escherichia coli counterpart, as E. coli PDH has been reported to be functional under aerobic conditions only. The resultant strain JS133 produced far less acetate with a further increased ethanol production, however, the glycolytic flux was still low. After observing differences in glycolytic flux for JS133 on glucose and fructose, we speculated that the pentose phosphate pathway (PPP) might be involved in the reduced flux on glucose. To prove this, we deleted the zwf gene, encoding glucose-6-phosphate dehydrogenase, which is the entry point into PPP, and immediately observed a stimulating effect on glycolysis. Subsequent characterization revealed a direct correlation between the intracellular NADH/NAD+ and NADPH/NADP+ ratios under anoxic conditions. Based on these findings we managed to re-channel the metabolism of C. glutamicum successfully towards either to ethanol or D-lactate with 92% and 98% of the theoretical yield respectively, which is the highest yields for D-lactate production thus far reported in the literature.

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