Ionizing radiation enhances therapeutic activity of mda-7/IL-24: overcoming radiation- and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2.
Subtraction hybridization applied to terminally differentiating human melanoma cells identified mda-7/IL-24, a cytokine belonging to the IL-10 gene superfamily. Adenoviral-mediated delivery of mda-7/IL-24 (Ad.mda-7) provokes apoptosis selectively in a wide spectrum of cancers in vitro in cell culture, in vivo in human tumor xenograft animal models and in patients with advanced carcinomas and melanomas. In human prostate cancer cells, a role for mitochondrial dysfunction and induction of reactive oxygen species in the apoptotic process has been established. Ectopic overexpression of bcl-xL and bcl-2 prevents these changes including apoptosis induction in prostate tumor cells by Ad.mda-7. We now document that this resistance to apoptosis can be reversed by treating bcl-2 family overexpressing prostate tumor cells with ionizing radiation in combination with Ad.mda-7 or purified GST-MDA-7 protein. Additionally, radiation augments apoptosis induction by mda-7/IL-24 in parental and neomycin-resistant prostate tumor cells. Radiosensitization to mda-7/IL-24 is dependent on JNK signaling, as treatment with the JNK 1/2/3 inhibitor SP600125 abolishes this effect. Considering that elevated expression of bcl-xL and bcl-2 are frequent events in prostate cancer development and progression, the present studies support the use of ionizing radiation in combination with mda-7/IL-24 as a means of augmenting the therapeutic benefit of this gene in prostate cancer, particularly in the context of tumors displaying resistance to radiation therapy owing to bcl-2 family member overexpression.
Su
Z-Z
ZZ
Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.
Lebedeva
I V
IV
Sarkar
D
D
Emdad
L
L
Gupta
P
P
Kitada
S
S
Dent
P
P
Reed
J C
JC
Fisher
P B
PB
D017209:Apoptosis; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D015316:Genetic Therapy; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000473:pathology / Q000628:therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D011836:Radiation Tolerance; D051020:bcl-X Protein / Q000032:analysis*; D000099180:Interleukin-24
D007378:Interleukins; D048031:JNK Mitogen-Activated Protein Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D000099180:Interleukin-24