Upregulation Of Pyruvate Dehydrogenase Kinase 3 Mediates Hypoxia-Induced Drug Resistance In Colon Cancer

Colorectal cancer is the second leading cause of cancer-related death in both male and female worldwide. Despite the efforts of screening and advances in treatment, 50% of patients with colon cancer will ultimately die from their disease. One major hurdle of treating colon cancer is its high recurrence due to resistance to anti-cancer therapy of hypoxic tumor, a survival advantage resulting from metabolic switch of cancer cells. The switch of cellular metabolism from mitochondrial respiration to glycolysis is the hallmark of cancer cells and is associated with tumor malignancy. Previous studies demonstrated that pyruvate dehydrogenase kinase-1 (PDK1) and PDK3 play an important role in the metabolic switch of cancer cells. Herein, we assessed the expression profile of PDK1 and PDK3 in colorectal cancer. Western blotting results demonstrated that levels of PDK3 were markedly upregulated in colon cancer compared to adjacent normal tissues while levels of PDK1 were decreased in cancer cells. Immunohistochemical staining (n=307) further revealed that expression of PDK3 was positively correlated with the level of hypoxia inducible factor-1α (HIF-1α) and the severity of cancer. Level of PDK3 was markedly induced by hypoxia in a HIF-1α dependent manner, while HIF-2α had no effect on PDK3 expression in colon cancer cell lines. Aberrant expression of PDK3 mediates hypoxia-induced drug resistance as knocking-down PDK3 by siRNA under hypoxia abolished such protective effect. Taken together, these data demonstrated that PDK3 is overexpressed in colon cancer and is associated with tumor malignancy. Our current findings provide novel insights about metabolic switch in cancer cells and suggest that PDK3 can be a new and pivotal target for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 988. doi:10.1158/1538-7445.AM2011-988