PKCalpha activation downregulates ATM and radio-sensitizes androgen-sensitive human prostate cancer cells in vitro and in vivo. Academic Article uri icon

Overview

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.

publication date

  • January 4, 2009

Research

keywords

  • Androgens
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Prostatic Neoplasms
  • Protein Kinase C-alpha
  • Protein Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases
  • Tumor Suppressor Proteins

Identity

PubMed Central ID

  • PMC3630174

Scopus Document Identifier

  • 66149158200

PubMed ID

  • 19029835

Additional Document Info

volume

  • 8

issue

  • 1