PIK3C3 regulates the expansion of liver CSCs and PIK3C3 inhibition counteracts liver cancer stem cell activity induced by PI3K inhibitor.

Cell Death & Disease
Fengchao LiuJian Gao

Abstract

The existence of cancer stem cells (CSCs) accounts for hepatocellular carcinoma (HCC) treatment resistance, relapse, and metastasis. Although the elimination of cancer stem cells is crucial for cancer treatment, strategies for their elimination are limited. Here, we report that a remarkable increase in PIK3C3 was detected in HCC tissues and liver CSCs. Upregulated PIK3C3 facilitated liver CSC expansion in HCC cells; RNA interference-mediated silencing of PIK3C3 had an opposite effect. Furthermore, PIK3C3 inhibition by inhibitors effectively eliminated liver CSCs and inhibited the growth of tumors in vivo. The phosphoinositide 3-kinase (PI3K) pathway is considered an important hallmark of cancer. One of our recent studies found that prolonged inhibition by inhibitors of class I PI3K induces liver CSCs expansion. To our surprise, PIK3C3 inhibition blocked the expansion of CSCs induced by PI3K inhibitor; moreover, treatment with the combination of PIK3C3 inhibitor and PI3K inhibitor in maximal suppresses the expansion of liver CSCs of tumors in mice. Mechanistically, inhibition of PIK3C3 inhibit the activation of SGK3, a CSCs promoter, induced by PI3K inhibitor. We also show that PIK3C3 inhibitor suppresses liver CSCs by activatio...Continue Reading

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Methods Mentioned

BETA
biosensor
transfection
FACS
xenograft
flow-cytometry

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