Melanoma differentiation associated gene-7/interleukin-24 promotes tumor cell-specific apoptosis through both secretory and nonsecretory pathways.
Melanoma differentiation associated gene-7/interleukin-24 (Mda-7/IL-24), a novel member of the IL-10 family of cytokines, uniquely displays cancer-specific apoptosis-inducing activity. Positive results in ongoing phase I/II clinical trials have strengthened the possibility of its utilization as a cancer gene therapeutic. Previous studies document that signaling events leading to Ad.mda-7-induced transformed cell apoptosis are tyrosine kinase-independent. These results suggest that mda-7/IL-24 cancer cell-specific activity could occur through mechanisms independent of binding to its currently recognized cognate receptors and might even occur independent of receptor function. An adenovirus vector expressing a nonsecreted version of MDA-7/IL-24 protein was generated via deletion of its signal peptide. This nonsecreted protein was as effective as wild-type secreted MDA-7/IL-24 in inducing apoptosis in prostate carcinoma cell lines and displayed transformed cell specificity and localization of MDA-7/IL-24 in the Golgi/endoplasmic reticulum compartments. Our results indicate that mda-7/IL-24-mediated apoptosis can be triggered through a combination of intracellular as well as secretory mechanisms and can occur efficiently in the absence of protein secretion.
Sauane
Moira
M
Department of Pathology, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York 10032, USA.
Lebedeva
Irina V
IV
Su
Zao-zhong
ZZ
Choo
Heng-tong
HT
Randolph
Aaron
A
Valerie
Kristoffer
K
Dent
Paul
P
Gopalkrishnan
Rahul V
RV
Fisher
Paul B
PB
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000099180:Interleukin-24
D007378:Interleukins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000099180:Interleukin-24