title: VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase-mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal.
abstract: Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis. Mechanistic studies point to the unresolved unfolded protein response (UPR) as a mechanism by which VCP inhibitors contribute to cytotoxicity. These results support an emerging concept that UPR and endoplasmic reticulum (ER) stress pathways may be targeted in ovarian cancer as a source of vulnerability. Since prolonged ER stress may result in CHOP-mediated cell death, we tested the hypothesis that VCP inhibitors act synergistically with compounds that enhance CHOP expression. Here, we show that VCP inhibitors act synergistically with Salubrinal, an inhibitor of eIF2α dephosphorylation, by enhancing CHOP expression in ovarian cancer cell lines. Our results provide a proof-of-concept that VCP inhibitors can be used as a single agent and can be synergized with compounds that enhance CHOP expression to induce cell death in ovarian cancer cells.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Bastola
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Neums
authors.affiliation: Higuchi Biosciences Center, University of Kansas, Lawrence, KS 66047, USA; Target Acceleration Group, University of Kansas Cancer Center, Kansas City, KS 66047, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Schoenen
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA. Electronic address: jchien@kumc.edu.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology*; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D000074405:Valosin Containing Protein
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D002934:Cinnamates; C000600804:ML240 compound; C558357:N2,N4-dibenzylquinazoline-2,4-diamine; D011799:Quinazolines; C496827:salubrinal; D020169:Caspases; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; D013890:Thiourea
keywords: CB-5083; DBeQ; ER stress; ML240; Ovarian cancer; Salubrinal; Synergy; Unfolded protein response