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

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.

The effect of transforming growth factor β1 on the crosstalk between autophagy and apoptosis in the annulus fibrosus cells under serum deprivation

“…Abundance of nutrients, including growth factors, glucose, and amino acids activate mTOR and suppress autophagy, whereas nutrient deprivation could inhibit mTOR and promote autophagy [21,63]. PI3K/AKT lay upstream of mTOR, and activated AKT inhibited autophagy through activating mTOR [64][65][66].…”

Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics

“…For instance, protective autophagy that is induced by benzyl isothiocyanate (BITC), a dietary chemo-preventive agent, induces apoptosis when 3-MA inhibits BITC-mediated autophagy [104]. The chemo-preventive effects of dietary phytochemicals on malignant tumors have been studied extensively due to a relative lack of toxicity.…”

Mechanisms of the Anticancer Effects of Isothiocyanates

“…Likewise, BITC also suppresses PI3K (Tyr-458), PDK1 (Ser-241), and mammalian target of rapamycin (mTOR) (Ser 2448) [16]. BITC also inhibits mTOR signaling in prostate cancer cells [28]. Importantly, these studies have shown that BITC has very negligible effect on the growth of normal human pancreatic ductal epithelial 6 cells, indicating specificity of BITC toward cancer cells.…”