ROS accumulation by PEITC selectively kills ovarian cancer cells via UPR-mediated apoptosis

Abstract

Unfolded protein response (UPR) is crucial for both survival and death of mammalian cells, which is regulated by reactive oxygen species (ROS) and nutrient depletion. In this study, we demonstrated the effect of ROS-accumulation, induced by β-phenethyl isothiocyanate (PEITC), on UPR-mediated apoptosis in ovarian cancer cells. We used ovarian cancer cell lines, PA-1 and SKOV-3, with different p53 status (wild- and null-type, respectively). PEITC caused increased ROS-accumulation and inhibited proliferation selectively in ovarian cancer cells, and glutathione (GSH) depletion in SKOV-3. However, PEITC did not cause any effect in normal ovarian epithelial cells and peripheral blood mononuclear cells. After 48 h of PEITC treatment (5 μM), apoptotic cell death was shown to increase significantly in the ovarian cancer cells and not in the normal cells. The key regulator of UPR-mediated apoptosis, CHOP/GADD153 and endoplasmic reticulum resident chaperone BiP/GRP78 were parallely up-regulated with activation of two major sensors of the UPR [PERK and ATF-6 in PA-1; PERK, and IRE1α in SKOV-3) in response to ROS accumulation induced by PEITC (5 μM). ROS scavenger, N-acetyl-L-cysteine (NAC), attenuated the effect of PEITC on UPR signatures (P-PERK, IRE1α, CHOP/GADD153, and BiP/GRP78), suggesting the involvement of ROS in UPR-mediated apoptosis. Altogether, PEITC induces UPR-mediated apoptosis in ovarian cancer cells via accumulation of ROS in a cancer-specific manner.

Phenethyl isothiocyanate suppresses the metastasis of ovarian cancer associated with the inhibition of CRM1-mediated nuclear export and mTOR-STAT3 pathway

“…Previous studies have elucidated possible molecular mechanisms, including apoptosis induction and proliferation inhibition. 31,32 In the current study, we verified that PEITC inhibited the migration and invasion of EOC in vitro and in vivo. We also explored the possible mechanisms of PEITC in EOC cell lines.…”

Tubeimoside-1 induces oxidative stress-mediated apoptosis and G0/G1 phase arrest in human prostate carcinoma cells in vitro

“…Recent research has shown that in contrast to the tumor-promoting ability of higher ROS levels, this biochemical property of cancer cells may have therapeutic benefits. Targeting mitochondria to increase the ROS level above a toxic threshold by exogenous ROS-generating phytochemicals to selectively kill cancer cells has been shown to be feasible in various in vitro and in vivo experimental models [29][30][31][32][33] . In the present study, TBMS1 increased ROS generation, modulated Bax and Bcl-2 expression, dissipated mitochondrial membrane potential and ultimately induced apoptosis in DU145 cells by inducing DNA fragmentation and caspase-3 cleavage in a dose-dependent manner.…”

“…Accumulating research suggests that cancer cells exhibit high oxidative stress compared with normal cells, which plays an important role in cancer cell survival, proliferation, disruption of cell death signaling, metastasis, angiogenesis, and drug resistance [29][30][31] . Recent research has shown that in contrast to the tumor-promoting ability of higher ROS levels, this biochemical property of cancer cells may have therapeutic benefits.…”

Phenethyl Isothiocyanate, a Dual Activator of Transcription Factors NRF2 and HSF1

“…By use of [ 14 C]‐PEITC and mass spectrometry, PEITC has been found to bind HSP70, which is a component of the HSP90 multi‐chaperone complex 61. Third, PEITC has been reported to induce the UPR62 and inhibit the 20S and 26S proteasomal subunits,63 where both of these conditions have been shown to induce the HSF1‐mediated HSR.…”