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PKCalpha 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 PKCalpha mediates the TPA effect on ATM expression, since ATM suppression and apoptosis induced by either TPA or diacylglycerol-lactone (DAG-lactone), both inducing PKCalpha activation,(2) are abrogated in LNCaP cells following transfection of a kinase-dead PKCalpha mutant (KD-PKCalpha). Similarly, KD-PKCalpha blocks the apoptotic response elicited by combination of TPA and radiation, whereas expression of constitutively active PKCalpha 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 PKCalpha 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 PKCalpha 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.
AuthorsJean-Philip Truman, Susan A Rotenberg, Ji-Hye Kang, Gabriel Lerman, Zvi Fuks, Richard Kolesnick, Victor E Marquez, Adriana Haimovitz-Friedman
JournalCancer biology & therapy (Cancer Biol Ther) Vol. 8 Issue 1 Pg. 54-63 (Jan 2009) ISSN: 1555-8576 [Electronic] United States
PMID19029835 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References
  • (1-(hydroxymethyl)-4-(4-methyl-3-(methylethyl)pentylidene)-3-oxo-2-oxolanyl)methyl 4-methyl-3-(methylethyl)pentanoate
  • Androgens
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • Valerates
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • Protein Kinase C-alpha
  • Tetradecanoylphorbol Acetate
  • 4-Butyrolactone
Topics
  • 4-Butyrolactone (analogs & derivatives, pharmacology)
  • Androgens (pharmacology)
  • Apoptosis (drug effects, radiation effects)
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins (genetics, metabolism)
  • Cell Division (drug effects, radiation effects)
  • Cell Line, Tumor
  • DNA-Binding Proteins (genetics, metabolism)
  • Down-Regulation (drug effects)
  • Enzyme Activation (drug effects, radiation effects)
  • Humans
  • Kinetics
  • Male
  • Prostatic Neoplasms (enzymology, pathology)
  • Protein Kinase C-alpha (metabolism)
  • Protein Serine-Threonine Kinases (genetics, metabolism)
  • Tetradecanoylphorbol Acetate (pharmacology)
  • Tumor Suppressor Proteins (genetics, metabolism)
  • Valerates (pharmacology)

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