Protein phosphatase PHLPP induces cell apoptosis and exerts anticancer activity by inhibiting Survivin phosphorylation and nuclear export in gallbladder cancer

TL;DR

This study shows that PHLPP, a tumor suppressor, induces apoptosis in gallbladder cancer by inhibiting Survivin, offering potential for new gene therapies.

Contribution

The study reveals a novel regulatory pathway involving PHLPP, Survivin, and miR-495 in gallbladder cancer.

Findings

PHLPP expression is reduced in gallbladder cancer tissues and cell lines.

PHLPP inhibits Survivin phosphorylation and nuclear export, promoting apoptosis.

miR-495 negatively regulates PHLPP, and its inhibition suppresses tumor growth in mice.

Abstract

Many factors regulate cancer cell apoptosis, among which Survivin has a strong anti-apoptotic effect and PHLPP is a tumor suppressor gene that can induce significant apoptosis. However, the relationship between PHLPP and Survivin in gallbladder carcinoma (GBC) has not been reported. This study found that PHLPP expression is decreased and Survivin expression is increased in GBC tissues and cell lines. Their expression levels showed an inverse relationship and were associated with poor prognosis of GBC patients. Loss of PHLPP can increase the level of phosphorylated Survivin and induce the nuclear export of Survivin, which thus inhibit cell apoptosis and promote cell proliferation in GBC cells. The process that PHLPP regulates Survivin phosphorylation and intracellular localization is involved in AKT activity. Re-overexpression of PHLPP in GBC cells can decrease AKT phosphorylation level. Reduced expression of PHLPP in GBC is associated with high expression of miR-495. Increasing PHLPP expression or inhibiting miR-495 expression can induce apoptosis and suppress tumor growth in GBC xenograft model in nude mice. The results revealed the role and mechanism of PHLPP and Survivin in GBC cells and proposed strategies for gene therapies targeting the miR-495 / PHLPP / AKT / Survivin regulatory pathway.

Figures