PT  - JOURNAL ARTICLE
AU  - Yacoub, Adly
AU  - Liu, Renyan
AU  - Park, Margaret A
AU  - Hamed, Hossein A
AU  - Dash, Rupesh
AU  - Schramm, Danielle N
AU  - Sarkar, Devanand
AU  - Dimitriev, Igor P
AU  - Bell, Jessica K
AU  - Grant, Steven
AU  - Farrell, Nicholas P
AU  - Curiel, David T
AU  - Fisher, Paul B
AU  - Dent, Paul
TI  - Cisplatin enhances PERK- and CD95-dependent MDA-7/IL-24-induced killing in ovarian carcinoma cells
AID  - 10.1124/mol.109.061820
DP  - 2009 Nov 12
TA  - Molecular Pharmacology
PG  - mol.109.061820
4099  - http://molpharm.aspetjournals.org/content/early/2009/11/11/mol.109.061820.short
4100  - http://molpharm.aspetjournals.org/content/early/2009/11/11/mol.109.061820.full
AB  - 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