TY - JOUR T1 - Cisplatin enhances PERK- and CD95-dependent MDA-7/IL-24-induced killing in ovarian carcinoma cells JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.061820 SP - mol.109.061820 AU - Adly Yacoub AU - Renyan Liu AU - Margaret A Park AU - Hossein A Hamed AU - Rupesh Dash AU - Danielle N Schramm AU - Devanand Sarkar AU - Igor P Dimitriev AU - Jessica K Bell AU - Steven Grant AU - Nicholas P Farrell AU - David T Curiel AU - Paul B Fisher AU - Paul Dent Y1 - 2009/11/12 UR - http://molpharm.aspetjournals.org/content/early/2009/11/11/mol.109.061820.abstract N2 - Melanoma differentiation associated gene-7/interleukin 24 (mda-7/IL-24) is a unique IL-10 family cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on defining the mechanism(s) by which recombinant adenoviral delivery of MDA-7/IL-24 inhibits cell survival of human ovarian carcinoma cells (OCC). Expression of MDA-7/IL-24 induced phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eIF2α. In a PERK-dependent fashion MDA-7/IL-24 reduced ERK1/2 and AKT phosphorylation and activated JNK1/2 and p38 MAPK. MDA-7/IL-24 reduced MCL-1 and BCL-XL and increased BAX levels via PERK signaling; cell killing was mediated via the intrinsic pathway and cell killing was primarily necrotic as judged using Annexin V-PI staining. Inhibition of p38 MAPK and JNK1/2 abolished MDA-7/IL-24 toxicity and blocked BAX and BAK activation, whereas activation of MEK1/2 or AKT suppressed enhanced killing and JNK1/2 activation. MEK1/2 signaling increased expression of the MDA-7/IL-24 and PERK chaperone BiP/GRP78, and over-expression of BiP/GRP78 suppressed MDA-7/IL-24 toxicity. MDA-7/IL-24-induced LC3-GFP vesicularization and processing of LC3; and knockdown of ATG5 suppressed MDA-7/IL-24-mediated toxicity. MDA-7/IL-24 and cisplatin interacted in a greater than additive fashion to kill tumor cells that was dependent upon a further elevation of JNK1/2 activity and recruitment of the extrinsic CD95 pathway. MDA-7/IL-24 toxicity was enhanced in a weak additive fashion by paclitaxel; paclitaxel enhanced MDA-7/IL-24 + cisplatin lethality in a greater than additive fashion via BAX. Collectively, our data demonstrate that MDA-7/IL-24 induces an ER stress response that activates multiple pro-apoptotic pathways culminating in decreased ovarian tumor cell survival.The American Society for Pharmacology and Experimental Therapeutics ER -