Article Text

Download PDFPDF

337 Treatment of ovarian cancer via induction of cellular stress and the unfolded protein response (UPR)
  1. A Paridon,
  2. A Alvero,
  3. M Rumman and
  4. I Winer
  1. Detroit Medical Center/Wayne State University, USA


Introduction Ovarian 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.

Methods Patient-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.

Results Celastrol 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.

Conclusions Activating 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.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.