337 Treatment of ovarian cancer via induction of cellular stress and the unfolded protein response (UPR)

• Published in: International journal of gynecological cancer Vol. 30; no. Suppl 3; pp. A136 - A137
• Main Authors: Paridon, A, Alvero, A, Rumman, M, Winer, I
• Format: Journal Article
• Language: English
• Published: Oxford BMJ Publishing Group LTD 01.11.2020
• Subjects: Cytotoxicity; Ovarian cancer; Proteins
• ISSN: 1048-891X; 1525-1438
• DOI: 10.1136/ijgc-2020-IGCS.289

IntroductionOvarian cancer (OVCA) is a lethal gynecologic malignancy. Patients with high-grade and low-grade disease carry a poor prognosis from chemoresistance and decreased induction of apoptosis. We hypothesized persistent activation of the unfolded protein response (UPR) with upregulation of CHOP and XAF-1 arms, would overcome apoptotic arrest, leading to death in chemo-sensitive and resistant OVCA.MethodsPatient-derived and commercially available HG and LG OVCA cells were cultured and treated with celastrol, a potent UPR activator. Cell viability was assessed using Incucyte. Protein lysates of cells treated with celastrol were analyzed using Western blot and Caspase-Glo. RNA was analyzed using real-time PCR. Transient knock down (KD) of XAF-1 and CHOP was performed using siRNA.ResultsCelastrol induced cell death in chemo-sensitive and resistant OVCA lines in the nanomolar range. Celastrol induced the UPR.CHOP was preferentially upregulated upstream of mitochondrial depolarization and induction of the intrinsic apoptotic pathway. There was a reciprocal rise in XAF-1 RNA/protein levels and fall in XIAP with UPR activation. KD of XAF-1 decreased the cytotoxic effect of celastrol. KD of CHOP resulted in a lack of rise in XAF-1 with UPR activation.Abstract 337 Figure 1ConclusionsActivating UPR with agents that upregulate the CHOP/XAF-1 axis induce death in chemo-sensitive/resistant OVCA lines. XAF-1 is presumptively regulated by CHOP and a major effector of UPR, required for full cytotoxic activity. The CHOP/XAF-1 arm of UPR is a promising targetable pathway for treating HG/LG OVCA.