Drug resistance often limits the outcome and efficacy of chemoprevention as well as chemotherapy.  In addition to the ATP-dependent drug transporter, phosphatidylinositide 3-kinase (PI3K) is one of the plausible molecules that mediate drug resistance.  The activation of PI3K, leading to the activation of a variety of downstream targets including Akt, FoxO1 and mTOR, influences cell growth, survival and drug resistance in a variety of human cancer cells.  Thus, the PI3K/Akt/FoxO pathway is one of the most attractive targets to improve the therapeutic and preventive efficacy of anti-cancer agents.  Organosulfur compounds including isothiocyanates (ITCs) are an important and promising group of compounds that have a cancer-preventive property.  Benzyl isothiocyanate (BITC), an ITC compound mainly derived from cruciferous vegetables, inhibits cancer cell proliferation by inducing cell cycle arrest and apoptosis.  However, the regulating role of the PI3K/Akt/FoxO pathway in antiproliferation by BITC in human colorectal cancer cells remains unclear.  We initially examined the effect of BITC on the PI3K/Akt/FoxO1 survival pathway in human colorectal cancer cells.  Unexpectedly, BITC activated the PI3K/Akt/FoxO survival pathway, even though it significantly inhibited the cell proliferation.  Inhibitory experiments using PI3K selective inhibitors significantly enhanced the BITC-induced apoptosis with the inhibition of the PI3K/Akt/FoxO pathway.  BITC enhanced the insulin-activated PI3K/Akt/FoxO pathway, possibly through the inhibition of the protein tyrosine phosphatase 1B enzymatic activity.  We have also observed that BITC induced autophagy, concomitantly with Nrf2 up-regulation in human colorectal cancer cells.  Experiments using a PI3K inhibitor suggested that PI3K is involved not only in the accumulation of autophagic molecules, but also the up-regulation of p62 and Nrf2.  Taken together, PI3K might play pivotal roles not only in the resistant mechanism against BITC through inhibition of apoptosis, but also autophagy-dependent up-regulation of cytoprotective enzymes in human colon cancer cells.  These findings further proposed that combinatory treatment with the PI3K inhibitors is a promising strategy to overcome resistance of food phytochemicals as well as anti-cancer agents, activating PI3K in human colon cancer cells.

Involvement of the phosphatidylinositide 3-kinase pathway in the resistant mechanisms against benzyl isothiocyanate in human colorectal cancer cells

256th National Meeting (2018)

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