PT  - JOURNAL ARTICLE
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
TI  - Cisplatin Enhances Protein Kinase R-Like Endoplasmic Reticulum Kinase- and CD95-Dependent Melanoma Differentiation-Associated Gene-7/Interleukin-24–Induced Killing in Ovarian Carcinoma Cells
AID  - 10.1124/mol.109.061820
DP  - 2010 Feb 01
TA  - Molecular Pharmacology
PG  - 298--310
VI  - 77
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/77/2/298.short
4100  - http://molpharm.aspetjournals.org/content/77/2/298.full
SO  - Mol Pharmacol2010 Feb 01; 77
AB  - Melanoma differentiation associated gene-7/interleukin 24 (mda-7/IL-24) is a unique interleukin (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. Expression of MDA-7/IL-24 induced phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor2α (eIF2α). In a PERK-dependent fashion, MDA-7/IL-24 reduced ERK1/2 and AKT phosphorylation and activated c-Jun NH2-terminal kinase (JNK) 1/2 and p38 mitogen-activated protein kinase (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/propidium iodide staining. Inhibition of p38 MAPK and JNK1/2 abolished MDA-7/IL-24 toxicity and blocked BAX and BAK activation, whereas activation of mitogen-activated extracellular-regulated kinase (MEK) 1/2 or AKT suppressed enhanced killing and JNK1/2 activation. MEK1/2 signaling increased expression of the MDA-7/IL-24 and PERK chaperone BiP/78-kDa glucose regulated protein (GRP78), and overexpression of BiP/GRP78 suppressed MDA-7/IL-24 toxicity. MDA-7/IL-24-induced LC3-green fluorescent protein 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 on 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 endoplasmic reticulum stress response that activates multiple proapoptotic pathways, culminating in decreased ovarian tumor cell survival.