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Na/K-ATPase Y260 Phosphorylation-mediated Src Regulation in Control of Aerobic Glycolysis and Tumor Growth.

ABSTRACT: We report here the identification of ?1 Na/K-ATPase as a major regulator of the proto-oncogene Src kinase and the role of this regulation in control of Warburg effect and tumor growth. Specifically, we discovered Y260 in ?1 Na/K-ATPase as a Src-specific phosphorylation and binding site and that Y260 phosphorylation is required for Src-mediated signal transduction in response to a number of stimuli including EGF. As such, it enables a dynamic control of aerobic glycolysis. However, such regulation appears to be lost or attenuated in human cancers as the expression of Na/K-ATPase ?1 was significantly decreased in prostate, breast and kidney cancers, and further reduced in corresponding metastatic lesions in patient samples. Consistently, knockdown of ?1 Na/K-ATPase led to a further increase in lactate production and the growth of tumor xenograft. These findings suggest that ?1 Na/K-ATPase works as a tumor suppressor and that a loss of Na/K-ATPase-mediated Src regulation may lead to Warburg phenotype in cancer.

SUBMITTER: Banerjee M

PROVIDER: S-EPMC6098021 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Na/K-ATPase Y260 Phosphorylation-mediated Src Regulation in Control of Aerobic Glycolysis and Tumor Growth.

Banerjee Moumita M Cui Xiaoyu X Li Zhichuan Z Yu Hui H Cai Liquan L Jia Xuelian X He Daheng D Wang Chi C Gao Tianyan T Xie Zijian Z

Scientific reports 20180817 1

We report here the identification of α1 Na/K-ATPase as a major regulator of the proto-oncogene Src kinase and the role of this regulation in control of Warburg effect and tumor growth. Specifically, we discovered Y260 in α1 Na/K-ATPase as a Src-specific phosphorylation and binding site and that Y260 phosphorylation is required for Src-mediated signal transduction in response to a number of stimuli including EGF. As such, it enables a dynamic control of aerobic glycolysis. However, such regulatio ...[more]

PMID: 30120256

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Project description:BackgroundProstate cancer (PCa), one of the common malignant tumors, is the second leading cause of cancer-related deaths in men. The circadian rhythm plays a critical role in disease. Circadian disturbances are often found in patients with tumors and enable to promote tumor development and accelerate its progression. Accumulating evidence suggests that the core clock gene NPAS2 (neuronal PAS domain-containing protein 2) has been implicated in tumors initiation and progression. However, there are few studies on the association between NPAS2 and prostate cancer. The purpose of this paper is to investigate the impact of NPAS2 on cell growth and glucose metabolism in prostate cancer.MethodsQuantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) staining, western blot, GEO (Gene Expression Omnibus) and CCLE (Cancer Cell Line Encyclopedia) databases were used to analyze the expression of NPAS2 in human PCa tissues and various PCa cell lines. Cell proliferation was assessed using MTS, clonogenic assays, apoptotic analyses, and subcutaneous tumor formation experiments in nude mice. Glucose uptake, lactate production, cellular oxygen consumption rate and medium pH were measured to examine the effect of NPAS2 on glucose metabolism. The relation of NPAS2 and glycolytic genes was analyzed based on TCGA (The Cancer Genome Atlas) database.ResultsOur data showed that NPAS2 expression in prostate cancer patient tissue was elevated compared with that in normal prostate tissue. NPAS2 knockdown inhibited cell proliferation and promoted cell apoptosis in vitro and suppressed tumor growth in a nude mouse model in vivo. NPAS2 knockdown led to glucose uptake and lactate production diminished, oxygen consumption rate and pH elevated. NPAS2 increased HIF-1A (hypoxia-inducible factor-1A) expression, leading to enhanced glycolytic metabolism. There was a positive correlation with the expression of NPAS2 and glycolytic genes, these genes were upregulated with overexpression of NPAS2 while knockdown of NPAS2 led to a lower level.ConclusionNPAS2 is upregulated in prostate cancer and promotes cell survival by promoting glycolysis and inhibiting oxidative phosphorylation in PCa cells.

Dataset Information

Na/K-ATPase Y260 Phosphorylation-mediated Src Regulation in Control of Aerobic Glycolysis and Tumor Growth.

Publications

Na/K-ATPase Y260 Phosphorylation-mediated Src Regulation in Control of Aerobic Glycolysis and Tumor Growth.

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