期刊
CANCER BIOLOGY & THERAPY
卷 8, 期 1, 页码 54-63出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.8.1.7119
关键词
ionizing radiation; ATM; apoptosis; prostate; PKC alpha
类别
资金
- NIH [RO1 CA105125, ROI CA85704]
- The Virginia and D.K. Ludwig Fund for Cancer Research
- National Cancer Institute
- Center for Cancer Research
- NATIONAL CANCER INSTITUTE [R01CA085704, R01CA105125, ZIABC010942] Funding Source: NIH RePORTER
We previously demonstrated that treatment of human androgen-responsive prostate cancer cell lines LNCaP and CWR22-Rvl with 12-O-tetradecanoylphorbol 13-acetate (TPA), a known protein kinase C (PKC) activator, decreases ATM protein levels, thus de-repressing the enzyme ceramide synthase (CS) and promoting apoptosis as well as radio-sensitizing these cefls.(1) Here we show that PKC(x mediates the TPA effect on ATM expression, since ATM suppression and apoptosis induced by either TPA or diacylglycerol-lactone (DAG-lactone), both inducing PKC alpha activation,(2) are abrogated in LNCaP cells following transfection of a kinase-dead PKC alpha mutant (KD-PKC alpha). Similarly, KD-PKC alpha blocks the apoptotic response elicited by combination of TPA and radiation, whereas expression of constitutively active PKC alpha is sufficient to sensitize cells to radiation alone, without a need to pre-treat the cells with TPA. These findings identify CS activation as a downstream event of PKC alpha activity in LNCaP cells. Similar results were obtained in CWR22-Rvl cells with DAG-lactone treatment. Using the LNCaP orthotopic prostate model it is shown that treatment with TPA or DAG-lactone induces significant reduction in tumor ATM levels coupled with tumor growth delay. Furthermore, while fractionated radiation alone produces significant tumor growth delay, pretreatment with TPA or DAG-lactone significantly potentiates tumor cure. These findings support a model in which activation of PKC alpha downregulates ATM, thus relieving CS repression by ATM and enhancing apoptosis via ceramide generation. This model may provide a basis for the design of new therapies in prostate cancer.
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