Abstract 3910: Tetrandrine inhibits signal transduction through PI3K/Akt/mTOR and PERK/eIF2á pathways to target aberrantly activated cap-dependent translation in cancer cells

Abstract

Abstract The PI3K/Akt/mTOR pathway plays a key role in the control of cap-dependent mRNA translation and is also an important driver of tumor progression. Owing to mutations in PTEN across pan cancer, this pathway is activated in several solid tumors. mTOR signaling enhances tumor growth by stimulating both the global translation rates and the translation of a selected subset of sensitive transcripts, including mRNAs, encoding oncogenes, growth factors, anti-apoptotic factors - c-Myc, ornithine decarboxylase, Cyclin D1, VEGF, IGF, BCL-2, and survivin in several solid tumors. The foregoing data demonstrate that abnormal translational control in cancer, implemented by oncogenic signaling via mTOR and other pathways, may represent an attractive therapeutic target. Tetrandrine (Tet) a bis-benzylisoquinoline alkaloid with broad anticancer activity attracts increasing attention lately. However, the underlying molecular mechanisms were not studied systematically. In the present studies, we evaluated the effects of Tet on aberrantly activated cap-dependent translation and on its principal regulator - Akt / mTOR signaling pathway in cancer cells for the first time in any system. The anti-proliferative effects of Tet was evaluated in several cancer cell lines (LNCaP, 22Rv1, BXPC3, MiaPaCa2, A498, UOK262 HCC827, etc) representing many solid tumors. Using capped mRNA reporter construct, we evaluated the effect of Tet on translation in 22Rv1 and LNCaP PC cell cultures. We found that Tet was not able to inhibit translation of mRNA on the ribosomes per se in the in vitro translation system. However, Tet was operational in LNCaP and 22Rv1 cells, inhibiting cap-dependent translation rapidly and efficiently during the first few hours. A subsequent study of the polysomal distribution in LNCaP and 22Rv1 cells showed that Tet mainly inhibited the initiation phase of translation. Importantly, the translation-inhibiting effect of Tet correlated with its growth-suppressive activity in concentration and time-dependent manner. Our study of the PI3K/Akt signaling showed that Tet inhibited signaling to mTOR and its downstream effectors in PC cells. This explains the inhibition of cap-dependent mRNA translation and the suppression of cancer growth. Collectively, presented results show a new, previously unknown “translation side” of the anticancer activity of Tet. This novel insight may help with potential therapeutic applications of Tet in the treatment of cancer in general and prostate cancer in particular. Citation Format: Sergey Slepenkov, Praveen Jaiswal, Sweaty Koul, Hari K. Koul. Tetrandrine inhibits signal transduction through PI3K/Akt/mTOR and PERK/eIF2á pathways to target aberrantly activated cap-dependent translation in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3910.