Inhibition of Gli1‑mediated prostate cancer cell proliferation by inhibiting the mTOR/S6K1 signaling pathway

Yang,Hong; Hu,Libing; Liu,Zhimin; Qin,Yang; Li,Ruiqian; Zhang,Guoying; Zhao,Bin; Bi,Chengwei; Lei,Yonghong; Bai,Yu

doi:10.3892/ol.2017.7254

Inhibition of Gli1‑mediated prostate cancer cell proliferation by inhibiting the mTOR/S6K1 signaling pathway

Authors:
- Hong Yang
- Libing Hu
- Zhimin Liu
- Yang Qin
- Ruiqian Li
- Guoying Zhang
- Bin Zhao
- Chengwei Bi
- Yonghong Lei
- Yu Bai
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Affiliations: Department of Urology, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
Published online on: October 23, 2017 https://doi.org/10.3892/ol.2017.7254
Pages: 7970-7976

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Abstract

Ectopic activation of the canonical Hedgehog signaling pathway is involved in the development and progression of prostate cancer, which is one of the leading causes of cancer‑associated mortality in males worldwide. However, the role of the non‑canonical Hedgehog signaling pathway in prostate cancer remains generally unexplored. In the present study, it was identified that Gli (glioma‑associated oncogene)1 and Gli2 were highly expressed at the protein level in the androgen‑independent prostate cancer cell lines PC3 and DU145, but not in the androgen‑dependent cancer cell line LNCaP. Silencing of Gli1 using small interfering RNA markedly decreased PC3 cell viability and liquid colony formation in vitro. The Gli1/2‑specific inhibitor GANT61 markedly decreased cell viability by inducing cell apoptosis in PC3 and DU145 cells. GANT61 also alleviated liquid colony formation efficiency in PC3 and DU145 cells, suggesting that the activity of Gli1 is required for prostate cancer cell survival. To explore further the upstream signaling pathway involved in the regulation of Gli1 expression, it was identified that tumor necrosis factor α‑triggered mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase 1 (S6K1) activation was required for Gli1 expression. Pharmacological and genetic inhibition of S6K1 activation markedly decreased Gli1 and its downstream target gene mRNA expression. In addition, the phosphoinositide 3‑kinase/mTOR inhibitor BEZ235 markedly decreased in vitro PC3 cell proliferation. The results of the present study indicate that the non‑canonical Hedgehog pathway (mTOR/S6K1/Gli1) contributes to the development and progression of prostate cancer and that Gli1 is a potential therapeutic target in the treatment of prostate cancer.

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