Abstract

Mammalian target of rapamycin (mTOR) has merged an important therapeutic target for cancers. Our object is to demonstrate that phenyhexyle isothiocyanate (PHI), a synthetic isothiocyanate, blocked Akt/mTOR signaling in prostate cancer PC3 cell line, in addition to inhibited histone deacetylase to induce cell apoptosis. Apoptotic cells were measured by TUNEL assay. Histone acetylated H3, H4 and the protein of Akt signaling pathway (Akt, p-Akt, mTOR, p-mTOR, p70S6K, p-p70S6K) and apoptosis pathway (caspase-3, caspase-9, MCL-1, Cyt-1, XIAP) were detected by Western Blot. Apoptotic cells were increased after exposure to PHI with a concentration dependent manner. PHI significantly induced an accumulation of histone acetylated H3, H4, as assessed by decreased levels of the phosphorylated (p)-Akt, p-p70 ribosomal S6 kinase (p70S6K) and p-S6K after exposure to PHI for 7 h. The change of proteins of Akt, mTOR, p70S6K was not seen. PHI induced apoptosis through intrinsic pathway. PHI increases histone acetylated H3, H4, which activates gene transcription, induces tumor cell apoptosis. PHI induces Akt dephosphorylation, thus blocking Akt signaling pathway, which is an important therapeutics target.

Key words: Phenyhexyle isothiocyanate (PHI), prostate cancer, Akt/mammalian target of rapamycin (mTOR) , histone deacetylase, inhibitor.