Cystine Dimethyl Ester Induces Apoptosis Through Regulation of PKC-delta and PKC-epsilon in Prostate Cancer Cells

Gurbuz N., Park M. A., Dent P., Mageed A. B. A., Sikka S. C., Baykal A.

ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, cilt.15, sa.2, ss.217-227, 2015 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 15 Sayı: 2
  • Basım Tarihi: 2015
  • Doi Numarası: 10.2174/1871520614666141120121901
  • Dergi Adı: ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.217-227
  • Anahtar Kelimeler: Apoptosis, cancer, CDME, cystine, PKC-delta, PKC-epsilon, prostate, tumor prevention, PROTEIN-KINASE-C, ACTIVATION, EXPRESSION, TARGET, THIOLS, ASSAY
  • Akdeniz Üniversitesi Adresli: Evet

Özet

Protein kinase C-delta (PKC-delta) and PKC-epsilon are reported to be effective in cancer prevention via S-thiolationmediated mechanisms. This may be through stimulation of the pro-apoptotic, tumor-suppressive isozyme PKC-delta and/or inactivation of the growth stimulatory, oncogenic isozyme PKC-epsilon. We investigated oxidative regulatory responses of PKC-delta and PKC-epsilon to cystine dimethyl ester (CDME), a metabolic precursor of cystine, which, by inducing release of cellular cystine stimulates apoptosis in different prostate cancer cells, PC3 and LNCaP, compared to normal RWPE1 cells. Treatment of CDME in doses of 0.5mM and 5mM significantly induces apoptosis due to regulation of concentration-dependent PKC-delta stimulation and PKC-epsilon reduction in these prostate cancer cells. This apoptotic regulation was confirmed by immunoblot analyses and specific PKC enzyme assays in immunoprecipitated samples. Additionally, inhibition of PKC-delta by small interfering RNA (siRNA) proved that CDME-induced cell death was dependent on PKC-delta activity in prostate cancer cells. These data demonstrated that CDME induces apoptosis by cysteinylation of both PKC-delta and PKC-epsilon in tumorigenic prostate epithelial cells compared to control nontumorigenic cells. Cellular cystine may play a critical role in treatment and/or prevention of prostate cancer by regulating PKC activity.