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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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. Furthermore, we observed that combination treatment with RAME and cisplatin greatly enhanced the anti-tumor effect in cisplatin-resistant cervical cancer cells, which was likely due to mTOR/S6K1 inhibition-mediated autophagy and apoptosis.

CONCLUSIONS:

Our findings suggest that inhibition of S6K1 by RAME can induce autophagy and apoptosis in cervical cancer cells, and provide a potential option for cervical cancer treatment, particularly when combined with cisplatin.

• Authors: Ki Hong Nam, Sang Ah Yi, Gibeom Nam, Jae Sung Noh, Jong Woo Park, Min Gyu Lee, Jee Hun Park, Hwamok Oh, Jieun Lee, Kang Ro Lee, Hyun-Ju Park, Jaecheol Lee, Jeung-Whan Han
• Journal: BMC cancer (BMC Cancer) Vol. 19 Issue 1 Pg. 773 (Aug 06 2019) ISSN: 1471-2407 [Electronic] England
• PMID: 31387554 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cinnamates
• Depsides
• Protein Kinase Inhibitors
• Small Molecule Libraries
• rosmarinic acid methyl ester
• Ribosomal Protein S6 Kinases, 70-kDa
• ribosomal protein S6 kinase, 70kD, polypeptide 1
• Cisplatin

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cinnamates (chemistry, pharmacology)
• Cisplatin (pharmacology)
• Depsides (chemistry, pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Gene Knockdown Techniques
• Humans
• Molecular Conformation
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Protein Binding
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors, chemistry, genetics)
• Small Molecule Libraries
• Structure-Activity Relationship
• Uterine Cervical Neoplasms