(R)-9bMS Inhibited the Protein Synthesis and Autophagy of Triple Negative Breast Cancer Cells via Regulating miR-4660/mTOR Axis

• Published in: Protein and peptide letters Vol. 30; no. 4; p. 295
• Main Authors: Bai, Xiangdong, Han, Guohui, Li, Feng, Li, Weina, Bu, Peng, Zhang, Huanhu, Xie, Jun
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2023
• Subjects: Autophagy; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs - genetics; MicroRNAs - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Protein-Tyrosine Kinases - pharmacology; TOR Serine-Threonine Kinases - metabolism; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; mTOR; breast cancer; protein synthesis; TNBC; miR-4660; (R)-9bMS
• ISSN: 1875-5305
• DOI: 10.2174/0929866530666230302150750

Unlike other subtypes of breast cancer, triple negative breast cancer (TNBC) exhibits aggressive and metastatic behaviors and a lack of effective targeted therapeutics. (R)-9bMS, a small-molecule inhibitor of the non-receptor tyrosine kinase 2 (TNK2), significantly inhibited TNBC cell growth; however, the functional mechanism of (R)-9bMS in TNBC remains largely unknown. To explore the functional mechanism of (R)-9bMS in TNBC. Cell proliferation, apoptosis and xenograft tumor growth assays were performed to evaluate the effects of (R)-9bMS on TNBC. The expression levels of miRNA and protein were detected by RTqPCR or western blot, respectively. Protein synthesis was determined by analyzing the polysome profile and S-met incorporation. (R)-9bMS attenuated TNBC cell proliferation, induced cell apoptosis, and inhibited xenograft tumor growth. Mechanism study indicated that (R)-9bMS upregulated the expression of miR-4660 in TNBC cells. The expression of miR-4660 is lower in TNBC samples than that of the non-cancerous tissues. miR-4660 overexpression inhibited TNBC cell proliferation by targeting the mammalian target of rapamycin (mTOR), which reduced mTOR abundance in TNBC cells. Consistent with the downregulation of mTOR, exposure of (R)-9bMS inhibited the phosphorylation of p70S6K and 4E-BP1, which consequently interrupted the total protein synthesis and autophagy of TNBC cells. These findings uncovered the novel working mechanism of (R)-9bMS in TNBC by attenuating mTOR signaling via up-regulating miR-4660. The potential clinical significance of (R)- 9bMS in TNBC treatment is interesting to explore.