Dual effects of glutathione-S-transferase pi on As2O3 action in prostate cancer cells: enhancement of growth inhibition and inhibition of apoptosis.
To determine the effects of glutathione-S-transferase pi (GSTpi) on the actions of As2O3, As2O3-induced growth inhibition and apoptosis was studied in three prostate cancer cell lines: DU-145, PC-3 and LNCaP cells. As2O3 inhibited cell proliferation of DU-145 and PC-3 cells (both cells express GSTpi), but not of LNCaP cells (which lack GSTpi expression) at concentrations below 1 microM. LNCaP cells stably transfected and expressed GSTpi (LNCaP/GSTpi) became sensitive to As2O3 growth inhibition. As2O3 arrested cell growth of DU-145, PC-3 and LNCaP/GSTpi cells in the G2/M phase of the cell cycle at low concentrations (<2 microM), but did not induce apoptosis. At higher concentrations (10-20 microM), As2O3 induced apoptosis in LNCaP cells, but not in DU-145 or PC-3 cells. The apoptosis induction due to As2O3 treatment of LNCaP cell correlated with the activation of JNK and p38 and induction of p53 protein. LNCaP/GSTpi cells became insensitive to As2O3-induced apoptosis with reduced JNK activition. These data indicate that GSTpi increases growth inhibition due to As2O3 treatment and prevents As2O3-induced apoptosis in prostate cancer cells. Therefore, it appears that As2O3 inhibits cell growth and induces apoptosis through different mechanisms.
Lu
Min
M
Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Xia
Lijuan
L
Luo
David
D
Waxman
Samuel
S
Jing
Yongkui
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D010087:Oxides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D001152:Arsenicals; D007527:Isoenzymes; D010087:Oxides; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D000077237:Arsenic Trioxide