Autocrine regulation of mda-7/IL-24 mediates cancer-specific apoptosis.
A noteworthy aspect of melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) as a cancer therapeutic is its ability to selectively kill cancer cells without harming normal cells. Intracellular MDA-7/IL-24 protein, generated from an adenovirus expressing mda-7/IL-24 (Ad.mda-7), induces cancer-specific apoptosis by inducing an endoplasmic reticulum (ER) stress response. Secreted MDA-7/IL-24 protein, generated from cells infected with Ad.mda-7, induces growth inhibition and apoptosis in surrounding noninfected cancer cells but not in normal cells, thus exerting an anti-tumor "bystander" effect. The present studies reveal a provocative finding that recombinant MDA-7/IL-24 protein can robustly induce expression of endogenous mda-7/IL-24, which generates the signaling events necessary for bystander killing. To evaluate the mechanism underlying this positive autocrine feedback loop, we show that MDA-7/IL-24 protein induces stabilization of its own mRNA without activating its promoter. Furthermore, this posttranscriptional effect depends on de novo protein synthesis. As a consequence of this autocrine feedback loop MDA-7/IL-24 protein induces sustained ER stress as evidenced by expression of ER stress markers (BiP/GRP78, GRP94, GADD153, and phospho-eIF2alpha) and reactive oxygen species production, indicating that both intracellular and secreted proteins activate similar signaling pathways to induce apoptosis. Thus, our results clarify the molecular mechanism by which secreted MDA-7/IL-24 protein (generated from Ad.mda-7-infected cells) exerts cancer-specific killing.
Sauane
Moira
M
Departments of Urology, Pathology, and **Neurosurgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Su
Zao-Zhong
ZZ
Gupta
Pankaj
P
Lebedeva
Irina V
IV
Dent
Paul
P
Sarkar
Devanand
D
Fisher
Paul B
PB
D017209:Apoptosis; D019898:Autocrine Communication; D024201:Bystander Effect; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005246:Feedback; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D020871:RNA Stability; D000099180:Interleukin-24
D000091342:Endoplasmic Reticulum Chaperone BiP; D007378:Interleukins; D000099180:Interleukin-24; C000717247:HSPA5 protein, human