BiP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis.
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a unique member of the IL-10 gene family that induces cancer-selective growth suppression and apoptosis in a wide spectrum of human cancers in cell culture and animal models. Additionally, recent clinical trials confirm safety and document significant clinical activity of mda-7/IL-24 in patients with diverse solid cancers and melanomas. Despite intensive study the molecular basis of tumor-cell selectivity of mda-7/IL-24 is not well characterized. Using deletion analysis, a specific mutant of MDA-7/IL-24, M4, consisting of amino acids 104 to 206, is described that retains the cancer-specific growth-suppressive and apoptosis-inducing properties of the full-length protein. Employing rationally designed mutational analysis, we show that MDA-7/IL-24 and M4 physically interact with BiP/GRP78 through their C and F helices, localize in the endoplasmic reticulum, and activate p38 MAPK and GADD gene expression, culminating in cancer-selective apoptosis. These studies provide novel mechanistic insights into the discriminating antitumor activity of MDA-7/IL-24 by elucidating BiP/GRP78 as a defined intracellular target of action and present an unparalleled opportunity to develop improved therapeutic versions of this cancer-specific apoptosis-inducing cytokine.
Gupta
Pankaj
P
Department of Pathology, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.
Walter
Mark R
MR
Su
Zao-zhong
ZZ
Lebedeva
Irina V
IV
Emdad
Luni
L
Randolph
Aaron
A
Valerie
Kristoffer
K
Sarkar
Devanand
D
Fisher
Paul B
PB
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics*; D016296:Mutagenesis; D009690:Nucleic Acid Conformation; D011467:Prostate / Q000166:cytology; D011995:Recombination, Genetic; D017384:Sequence Deletion; D000099180:Interleukin-24
D017931:DNA Primers; D004273:DNA, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007378:Interleukins; D018832:Molecular Chaperones; D000099180:Interleukin-24; C000717247:HSPA5 protein, human