Increased glycolysis is considered as one of the most important metabolic alterations adapted by cancer cells in order to generate high levels of glycolytic intermediates to support proliferation. PHLPP belongs to a novel family of Ser/Thr protein phosphatases. Our previous studies have shown that PHLPP serves as a tumor suppressor to inhibit cell proliferation, promote apoptosis and increase therapeutic sensitivity in colon cancer cells. Here, we further examined the role of PHLPP in regulating metabolic pathways in colon cancer. Our results showed that the rate of glucose consumption and lactate production was significantly increased in PHLPP knockdown colon cancer cells and in PHLPP knockout MEF cells. Metabolic analysis using Seahorse XF96 analyzer revealed that decreased PHLPP expression resulted in an increase in the extracellular acidification rate (ECAR) suggesting enhanced glycolysis. To determine the underlying molecular mechanism, we found that the Akt-mediated phosphorylation of HK2 was elevated in PHLPP knockdown colon cancer cells and the amount of mitochondria-associated hexokinase 2 (HK2) was increased. This is consistent with previous finding that Akt-mediated phosphorylation of HK2 increases its activity by promoting mitochondria translocation. Furthermore, PHLPP, Akt and HK2 were found in the same mitochondria fraction and PHLPP co-immunoprecipitated with HK2 in colon cancer cells. As HK2 is the key enzyme that determines the direction and magnitude of glucose flux, our studies identified PHLPP as a novel regulator of glucose metabolism by controlling Akt-mediated regulation of HK2 activity.

Note: This abstract was not presented at the meeting.

Citation Format: Xiaopeng Xiong, Yang-an Wen, Tianyan Gao. Loss of PHLPP expression promotes glycolysis in colon cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1178. doi:10.1158/1538-7445.AM2015-1178