The 2-oxoglutarate analog 3-oxoglutarate decreases normoxic hypoxia-inducible factor-1 alpha in cancer cells, induces cell death, and reduces tumor xenograft growth

The cellular response to hypoxia is primarily regulated by the hypoxia-inducible factors (HIFs). HIF-1 alpha is also a major mediator of tumor physiology, and its abundance is correlated with therapeutic resistance in a broad range of cancers. Accumulation of HIF-1 alpha under hypoxia is mainly controlled by the oxygen-sensing HIF prolyl 4-hydroxylases (EGLNs, also known as PHDs). Here, we identified a high level of normoxic HIF-1 alpha protein in various cancer cell lines. EGLNs require oxygen and 2-oxoglutarate for enzymatic activity. We tested the ability of several cell-permeable 2-oxoglutarate analogs to regulate the abundance of HIF-1 alpha protein. We identified 3-oxoglutarate as a potent regulator of HIF-1 alpha in normoxic conditions. In contrast to 2-oxoglutarate, 3-oxoglutarate decreased the abundance of HIF-1 alpha protein in several cancer cell lines in normoxia and diminished HIF-1 alpha levels independent of EGLN enzymatic activity. Furthermore, we observed that 3-oxoglutarate was detrimental to cancer cell survival. We show that esterified 3-oxoglutarate, in combination with the cancer chemotherapeutic drug vincristine, induces apoptosis and inhibits tumor growth in vitro and in vivo. Our data imply that a novel treatment strategy targeting HIF-1 alpha in combination with the use of existing cytotoxic agents could serve as potent, future antitumor chemotherapies.