PKCα activation downregulates ATM and radio-sensitizes androgen-sensitive human prostate cancer cells in vitro and in vivo Journal Article
| Authors: | Truman, J. P.; Rotenberg, S. A.; Kang, J. H.; Lerman, G.; Fuks, Z.; Kolesnick, R.; Marquez, V. E.; Haimovitz-Friedman, A. |
| Article Title: | PKCα activation downregulates ATM and radio-sensitizes androgen-sensitive human prostate cancer cells in vitro and in vivo |
| Abstract: | We previously demonstrated that treatment of human androgen-responsive prostate cancer cell lines LNCaP and CWR22-Rv1 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 cells.1 Here we show that PKCα mediates the TPA effect on ATM expression, since ATM suppression and apoptosis induced by either TPA or diacylglycerol-lactone (DAG-lactone), both inducing PKCα activation,<sup>2</sup> are abrogated in LNCaP cells following transfection of a kinase-dead PKCα mutant (KD-PKCα). Similarly, KD-PKCα blocks the apoptotic response elicited by combination of TPA and radiation, whereas expression of constitutively active PKCα 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 PKCα activity in LNCaP cells. Similar results were obtained in CWR22-Rv1 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 PKCα 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. ©2008 Landes Bioscience. |
| Keywords: | controlled study; protein expression; unclassified drug; dna binding protein; human cell; genetics; dna-binding proteins; androgen; nonhuman; mutant protein; cell cycle protein; mouse; metabolism; cell cycle proteins; cell division; apoptosis; animal experiment; animal model; down-regulation; in vivo study; enzyme activation; in vitro study; drug effect; enzymology; pathology; enzyme activity; cell line, tumor; protein serine threonine kinase; cancer model; radiation exposure; prostate cancer; prostatic neoplasms; prostate; genetic transfection; kinetics; radiation dose fractionation; protein-serine-threonine kinases; prostate tumor; tumor suppressor proteins; tumor cell line; transcription factor sp1; drug derivative; atm protein; ionizing radiation; down regulation; tumor growth; tumor suppressor protein; androgens; radiosensitization; cell strain lncap; ceramide; protein kinase c alpha; protein kinase c gamma; atm; pkcα; diacylglycerol derivative; diacylglycerol lactone; hk 654; jh131a 109; jh131e 153; lactone derivative; phorbol 13 acetate 12 myristate; sphingosine acyltransferase; (1 (hydroxymethyl) 4 (4 methyl 3 (methylethyl)pentylidene) 3 oxo 2 oxolanyl)methyl 4 methyl 3 (methylethyl)pentanoate; (1-(hydroxymethyl)-4-(4-methyl-3-(methylethyl)pentylidene)-3-oxo-2-oxolanyl)methyl 4-methyl-3-(methylethyl)pentanoate; gamma butyrolactone; valeric acid derivative; 4-butyrolactone; protein kinase c-alpha; tetradecanoylphorbol acetate; valerates |
| Journal Title: | Cancer Biology and Therapy |
| Volume: | 8 |
| Issue: | 1 |
| ISSN: | 1538-4047 |
| Publisher: | Taylor & Francis Group |
| Date Published: | 2009-01-01 |
| Start Page: | 54 |
| End Page: | 63 |
| Language: | English |
| PUBMED: | 19029835 |
| PROVIDER: | scopus |
| PMCID: | PMC3630174 |
| DOI: | 10.4161/cbt.8.1.7119 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 2" - "Export Date: 30 November 2010" - "Source: Scopus" |
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