Definition of a Novel Feed-Forward Mechanism for Glycolysis-HIF1? Signaling in Hypoxic Tumors Highlights Aldolase A as a Therapeutic Target.

ABSTRACT: The hypoxia-inducible transcription factor HIF1? drives expression of many glycolytic enzymes. Here, we show that hypoxic glycolysis, in turn, increases HIF1? transcriptional activity and stimulates tumor growth, revealing a novel feed-forward mechanism of glycolysis-HIF1? signaling. Negative regulation of HIF1? by AMPK1 is bypassed in hypoxic cells, due to ATP elevation by increased glycolysis, thereby preventing phosphorylation and inactivation of the HIF1? transcriptional coactivator p300. Notably, of the HIF1?-activated glycolytic enzymes we evaluated by gene silencing, aldolase A (ALDOA) blockade produced the most robust decrease in glycolysis, HIF-1 activity, and cancer cell proliferation. Furthermore, either RNAi-mediated silencing of ALDOA or systemic treatment with a specific small-molecule inhibitor of aldolase A was sufficient to increase overall survival in a xenograft model of metastatic breast cancer. In establishing a novel glycolysis-HIF-1? feed-forward mechanism in hypoxic tumor cells, our results also provide a preclinical rationale to develop aldolase A inhibitors as a generalized strategy to treat intractable hypoxic cancer cells found widely in most solid tumors. Cancer Res; 76(14); 4259-69. ©2016 AACR.

SUBMITTER: Grandjean G 

PROVIDER: S-EPMC5082982 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature