Identification of a novel S6K1 inhibitor, rosmarinic acid methyl ester, for treating cisplatin-resistant cervical cancer

BMC Cancer
Ki Hong NamJeung-Whan Han

Abstract

The mTOR/S6K1 signaling pathway is often activated in cervical cancer, and thus considered a molecular target for cervical cancer therapies. Inhibiting mTOR is cytotoxic to cervical cancer cells and creates a synergistic anti-tumor effect with conventional chemotherapy agents. In this study, we identified a novel S6K1 inhibitor, rosmarinic acid methyl ester (RAME) for the use of therapeutic agent against cervical cancer. Combined structure- and ligand-based virtual screening was employed to identify novel S6K1 inhibitors among the in house natural product library. In vitro kinase assay and immunoblot assay was used to examine the effects of RAME on S6K1 signaling pathway. Lipidation of LC3 and mRNA levels of ATG genes were observed to investigate RAME-mediated autophagy. PARP cleavage, mRNA levels of apoptotic genes, and cell survival was measured to examine RAME-mediated apoptosis. RAME was identified as a novel S6K1 inhibitor through the virtual screening. RAME, not rosmarinic acid, effectively reduced mTOR-mediated S6K1 activation and the kinase activity of S6K1 by blocking the interaction between S6K1 and mTOR. Treatment of cervical cancer cells with RAME promoted autophagy and apoptosis, decreasing cell survival rate. Furt...Continue Reading

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Citations

Oct 23, 2020·Ageing Research Reviews·Stephen F VatnerDorothy E Vatner
Sep 9, 2021·Phytotherapy Research : PTR·Stefhani Andrioli RomeroFernando Moreira Simabuco

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Methods Mentioned

BETA
X-ray
electrophoresis
PCR
co-immunoprecipitation assay
lipidation

Software Mentioned

MOLCAD
Sybyl
Surflex
Dock Geom
Dock
FlexS implanted
RAME
FlexS
ImageJ

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