期刊
ONCOGENE
卷 25, 期 16, 页码 2339-2348出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209271
关键词
mda-7/1L-24; prostate cancer; ionizing radiation; apoptosis; bcl-family
资金
- NCI NIH HHS [R01 CA88906, R01 CA72955, P01 CA104177, R01 CA097318, R01 CA098712] Funding Source: Medline
- NIDDK NIH HHS [DK52585] Funding Source: Medline
- NIGMS NIH HHS [GM60554] Funding Source: Medline
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. mda7) 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-x(L) 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 GSTMDA-7 protein. Additionally, radiation augments apoptosis induction by mda-7/IL-24 in parental and neomycin-resistant prostate tumor cells. Radiosensitization to mda7/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-x(L) 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-2family member overexpression.
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