Dataset Information

PHLPP regulates hexokinase 2-dependent glucose metabolism in colon cancer cells.

ABSTRACT: Increased glucose metabolism is considered as one of the most important metabolic alterations adapted by cancer cells in order to generate energy as well as high levels of glycolytic intermediates to support rapid proliferation. PH domain leucine-rich repeat protein phosphatase (PHLPP) belongs to a novel family of Ser/Thr protein phosphatases that function as tumor suppressors in various types of human cancer. Here we determined the role of PHLPP in regulating glucose metabolism in colon cancer cells. Knockdown of PHLPP increased the rate of glucose consumption and lactate production, whereas overexpression of PHLPP had the opposite effect. Bioenergetic analysis using Seahorse Extracelluar Flux Analyzer revealed that silencing PHLPP expression induced a glycolytic shift in colon cancer cells. Mechanistically, we found that PHLPP formed a complex with Akt and hexokinase 2 (HK2) in the mitochondrial fraction of colon cancer cells and knockdown of PHLPP enhanced Akt-mediated phosphorylation and mitochondrial localization of HK2. Depletion of HK2 expression or treating cells with Akt and HK2 inhibitors reversed PHLPP loss-induced increase in glycolysis. Furthermore, PHLPP knockdown cells became addicted to glucose as a major energy source in that glucose starvation significantly decreased cancer cell survival. As HK2 is the key enzyme that determines the direction and magnitude of glucose flux, our study identified PHLPP as a novel regulator of glucose metabolism by controlling HK2 activity in colon cancer cells.

SUBMITTER: Xiong X

PROVIDER: S-EPMC5253420 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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PHLPP regulates hexokinase 2-dependent glucose metabolism in colon cancer cells.

Xiong Xiaopeng X Wen Yang-An YA Mitov Mihail I MI C Oaks Mary M Miyamoto Shigeki S Gao Tianyan T

Cell death discovery 20170123

Increased glucose metabolism is considered as one of the most important metabolic alterations adapted by cancer cells in order to generate energy as well as high levels of glycolytic intermediates to support rapid proliferation. PH domain leucine-rich repeat protein phosphatase (PHLPP) belongs to a novel family of Ser/Thr protein phosphatases that function as tumor suppressors in various types of human cancer. Here we determined the role of PHLPP in regulating glucose metabolism in colon cancer ...[more]

PMID: 28179998

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Project description:Hypercholesterolemia is often correlated with obesity which is considered a risk factor for various cancers. With the growing population of hypercholesterolemic individuals, there is a need to understand the role of increased circulatory cholesterol or dietary cholesterol intake towards cancer etiology and pathology. Recently, abnormality in the blood cholesterol level of colon cancer patients has been reported. In the present study, we demonstrate that alteration in cholesterol levels (through a high-cholesterol or high-fat diet) increases the incidence of chemical carcinogen-induced colon polyp occurrence and tumor progression in mice. At the cellular level, low-density lipoprotein cholesterol (LDLc) and high-density lipoprotein cholesterol (HDLc) promote colon cancer cell proliferation by tuning the cellular glucose and lipid metabolism. Mechanistically, supplementation of LDLc or HDLc promotes cellular glucose uptake, and utilization, thereby, causing an increase in lactate production by colon cancer cells. Moreover, LDLc or HDLc upregulates aerobic glycolysis, causing an increase in total ATP production through glycolysis, and a decrease in ATP generation by OXPHOS. Interestingly, the shift in the metabolic status towards a more glycolytic phenotype upon the availability of cholesterol supports rapid cell proliferation. Additionally, an alteration in the expression of the molecules involved in cholesterol uptake along with the increase in lipid and cholesterol accumulation was observed in cells supplemented with LDLc or HDLc. These results indicate that colon cancer cells directly utilize the cholesterol associated with LDLc or HDLc. Moreover, targeting glucose metabolism through LDH inhibitor (oxamate) drastically abrogates the cellular proliferation induced by LDLc or HDLc. Collectively, we illustrate the vital role of cholesterol in regulating the cellular glucose and lipid metabolism of cancer cells and its direct effect on the colon tumorigenesis.

Dataset Information

PHLPP regulates hexokinase 2-dependent glucose metabolism in colon cancer cells.

Publications

PHLPP regulates hexokinase 2-dependent glucose metabolism in colon cancer cells.

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