RT Journal Article
SR Electronic
T1 Cisplatin enhances PERK- and CD95-dependent MDA-7/IL-24-induced killing in ovarian carcinoma cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.109.061820
DO 10.1124/mol.109.061820
A1 Yacoub, Adly
A1 Liu, Renyan
A1 Park, Margaret A
A1 Hamed, Hossein A
A1 Dash, Rupesh
A1 Schramm, Danielle N
A1 Sarkar, Devanand
A1 Dimitriev, Igor P
A1 Bell, Jessica K
A1 Grant, Steven
A1 Farrell, Nicholas P
A1 Curiel, David T
A1 Fisher, Paul B
A1 Dent, Paul
YR 2009
UL http://molpharm.aspetjournals.org/content/early/2009/11/11/mol.109.061820.abstract
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