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SGK1 inhibition induces autophagy-dependent apoptosis via the mTOR-Foxo3a pathway

Weiwei Liu1, Xuchu Wang1, Zhenping Liu2

  • 1Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.

British Journal of Cancer
|October 11, 2017
PubMed
Abstract

Insights

Inhibiting serum- and glucocorticoid-induced kinase 1 (SGK1) triggers cancer cell death by promoting autophagy and apoptosis through the mTOR-Foxo3a pathway, offering a novel therapeutic strategy for prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Serum- and glucocorticoid-induced kinase 1 (SGK1) inhibition shows potential in delaying cancer progression.
  • The precise mechanisms underlying SGK1's role in cancer remain largely unelucidated.

Purpose of the Study:

  • To investigate the cellular mechanisms through which SGK1 inhibition exerts anti-cancer effects.
  • To explore the role of autophagy and apoptosis in SGK1 inhibition-induced cell death in prostate cancer.

Main Methods:

  • Utilized GSK650394 treatment and SGK1 silencing/overexpression in prostate cancer cell lines and xenografts.
  • Employed techniques including flow cytometry, western blotting, immunofluorescence, electron microscopy, and immunohistochemistry.

Main Results:

  • SGK1 inhibition induced G2/M arrest, apoptosis, and autophagy.
  • Autophagy induction was found to precede apoptosis, as inhibiting autophagy attenuated SGK1 inhibition-induced apoptosis.
  • Suppression of mTOR and Foxo3a phosphorylation was critical for SGK1 inhibition's effects, involving pFoxo3a (S253)-LC3 and pFoxo3a (S253)-p27 interactions.
  • Dual inhibition of mTOR and SGK1 resulted in enhanced autophagy and synergistic cytotoxic effects.

Conclusions:

  • SGK1 inhibition demonstrates significant anti-tumor effects in prostate cancer models.
  • A novel mechanism reveals SGK1 inhibition induces autophagy-dependent apoptosis via the mTOR-Foxo3a pathway.

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