ROS Accumulation by PEITC Selectively Kills Ovarian Cancer Cells via UPR-Mediated Apoptosis.
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.
Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine , Seoul , South Korea ; WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University , Seoul , South Korea.
Yoon-Hee
YH
Hong
Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine , Seoul , South Korea.
Md Hafiz
MH
Uddin
Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine , Seoul , South Korea.
Untek
U
Jo
Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine , Seoul , South Korea ; WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University , Seoul , South Korea.
Boyun
B
Kim
Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine , Seoul , South Korea ; WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University , Seoul , South Korea.
Jiyoung
J
Song
Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital , Seongnam , South Korea.
Dong Hoon
DH
Suh
Department of Obstetrics and Gynecology, Seoul National University College of Medicine , Seoul , South Korea.
Hee Seung
HS
Kim
Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine , Seoul , South Korea ; WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University , Seoul , South Korea ; Department of Obstetrics and Gynecology, Seoul National University College of Medicine , Seoul , South Korea.
Yong Sang
YS
Song
apoptosis; ovarian cancer; reactive oxygen species; unfolded protein response; β-phenethyl isothiocyanate