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.

Abstract

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 factor2alpha (eIF2alpha). In a PERK-dependent fashion, MDA-7/IL-24 reduced ERK1/2 and AKT phosphorylation and activated c-Jun NH(2)-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.

• Authors: Adly Yacoub, Renyan Liu, Margaret A Park, Hossein A Hamed, Rupesh Dash, Danielle N Schramm, Devanand Sarkar, Igor P Dimitriev, Jessica K Bell, Steven Grant, Nicholas P Farrell, David T Curiel, Paul B Fisher, Paul Dent
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 77 Issue 2 Pg. 298-310 (Feb 2010) ISSN: 1521-0111 [Electronic] United States
• PMID: 19910452 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Interleukins
• fas Receptor
• interleukin-24
• PERK kinase
• eIF-2 Kinase
• Cisplatin

Topics

• Cell Death (drug effects, physiology)
• Cell Differentiation (drug effects, physiology)
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Drug Synergism
• Endoplasmic Reticulum (drug effects, enzymology, metabolism)
• Endoplasmic Reticulum Chaperone BiP
• Female
• Gene Transfer Techniques
• Humans
• Interleukins (administration & dosage, genetics, physiology)
• Ovarian Neoplasms (drug therapy, enzymology, metabolism)
• eIF-2 Kinase (metabolism)
• fas Receptor (metabolism)