Benzyl isothiocyanate induces protective autophagy in human prostate cancer cells via inhibition of mTOR signaling

Ji Fan Lin, Te Fu Tsai, Po Cheng Liao, Yi Hsuan Lin, Yi Chia Lin, Hung En Chen, Kuang Yu Chou, Yi-Sheng Huang

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Abstract

Benzyl isothiocyanate (BITC) is a dietary chemopreventive agent that inhibits the growth of various human cancer cells by causing apoptotic cell death. In this study, we demonstrate that BITC not only induces apoptosis but also induces autophagy in human hormone-sensitive (Rv1) and -refractory (PC3) prostate cancer cells. In BITC-treated cells, the induction of autophagy was detected by monitoring the processing of an autophagy marker protein, microtubule-associated protein 1 light chain 3 (LC3), the aggregation of LC3 into granular structures and the formation of acidic organelles. Inhibition of autophagy using 3-methyladenine increased BITC-induced apoptosis, whereas the administration of caspase inhibitor suppressed BITC-induced cell death. Our data also showed that BITC inhibits mammalian target of rapamycin (mTOR) kinase activity in a dose-dependent manner. The expression of phospho-mTOR (Ser2481), an indicator of mTOR intrinsic catalytic activity, and phospho-UNC-51-like kinase 1 (Ser757), a direct substrate of mTOR, were decreased in BITC-treated cells. However, the increased expression of phospho-mTOR (Ser2448), phospho-AKT (Ser473) and antiapoptotic Bcl-2 were detected only in PC3 cells at later stages of BITC treatment. Collectively, our results show that BITC induces a protective autophagy response in Rv1 and PC3 cells through inhibition of the mTOR signaling pathway. Activation of the AKT survival pathway was only observed in PC3 cells, representing a resistance mechanism of advanced prostate cancer upon BITC treatment. These findings could potentially contribute to the beneficial effect of BITC in prostate cancer treatments.

Original languageEnglish
Pages (from-to)406-414
Number of pages9
JournalCarcinogenesis
Volume34
Issue number2
DOIs
Publication statusPublished - Feb 2013

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ASJC Scopus subject areas

  • Cancer Research

Cite this

Lin, J. F., Tsai, T. F., Liao, P. C., Lin, Y. H., Lin, Y. C., Chen, H. E., Chou, K. Y., & Huang, Y-S. (2013). Benzyl isothiocyanate induces protective autophagy in human prostate cancer cells via inhibition of mTOR signaling. Carcinogenesis, 34(2), 406-414. https://doi.org/10.1093/carcin/bgs359