Type I? phosphatidylinositol phosphate kinase promotes tumor growth by facilitating Warburg effect in colorectal cancer.

ABSTRACT: BACKGROUND:Emerging evidence suggests that metabolic alterations are a hallmark of cancer cells and contribute to tumor initiation and development. Cancer cells primarily utilize aerobic glycolysis (the Warburg effect) to produce energy and support anabolic growth. The type I? phosphatidylinositol phosphate kinase (PIPKI?) is profoundly implicated in tumorigenesis, however, little is known about its role in reprogrammed energy metabolism. METHODS:Loss- and gain-of-function studies were applied to determine the oncogenic roles of PIPKI? in colorectal cancer. Transcriptome analysis, real-time qPCR, immunohistochemical staining, Western blotting, and metabolic analysis were carried out to uncover the cellular mechanism of PIPKI?. FINDINGS:In this study, we showed that PIPKI? was frequently upregulated in colorectal cancer and predicted a poor prognosis. Genetic silencing of pan-PIPKI? suppressed cell proliferation and aerobic glycolysis of colorectal cancer. In contrast, the opposite effects were observed by overexpression of PIPKI?_i2. Importantly, PIPKI?-induced prolific effect was largely glycolysis-dependent. Mechanistically, PIPKI? facilitated activation of PI3K/Akt/mTOR signaling pathways to upregulate c-Myc and HIF1? levels, which regulate expression of glycolytic enzymes to enhance glycolysis. Moreover, pharmacological inhibition by PIPKI? activity with the specific inhibitor UNC3230 significantly inhibited colorectal cancer glycolysis and tumor growth. INTERPRETATION:Our findings reveal a new regulatory role of PIPKI? in Warburg effect and provide a key contributor in colorectal cancer metabolism with potential therapeutic potentials. FUND: National Key Research and Development Program of China, Outstanding Clinical Discipline Project of Shanghai Pudong, Natural Science Foundation of China, and Science and Technology Commission of Shanghai Municipality.

SUBMITTER: Peng W 

PROVIDER: S-EPMC6604371 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature