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Glycogen Synthase Kinase 3β Regulates Cell Death Induced by Synthetic Triterpenoids

¹ Molecular Oncology and Angiogenesis Laboratory, Istituto Nazionale per la Ricerca sul Cancro (IST), Genova, Italy; ² Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire; and ³ Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica, Milan, Italy

Requests for reprints: Francesca Tosetti, Molecular Oncology and Angiogenesis Laboratory, Istituto Nazionale per la Ricerca sul Cancro (IST), Largo Rosanna Benzi 10, 16132 Genova, Italy. Phone: 39-10-5737411; Fax: 39-10-5737231; E-mail: francesca.tosetti{at}istge.it.

Key Words: 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid • CDDO • triterpenoids • prostate cancer • GSK3 • AKT • caspase-8

The induction of programmed cell death in premalignant or malignant cancer cells by chemopreventive agents could be a valuable tool to control prostate cancer initiation and progression. In this work, we present evidence that the C-28 methyl ester of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me) induces cell death in androgen-responsive and unresponsive human prostate cancer cell lines at nanomolar and low micromolar concentrations. CDDO-Me induced caspase-3, caspase-8, and caspase-9 activation; poly(ADP-ribose) polymerase cleavage; internucleosomal DNA fragmentation; and loss of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction in PC3 and DU145 cells. However, caspase-3 and caspase-8 inhibition by Z-DEVD-fmk and Z-IETD-fmk, respectively, or general caspase inhibition by BOC-D-fmk or Z-VAD-fmk did not rescue loss of cell viability induced by CDDO-Me, suggesting the activation of additional caspase-independent mechanisms. Interestingly, CDDO-Me induced inactivating phosphorylation at Ser⁹ of glycogen synthase kinase 3β (GSK3β), a multifunctional kinase that mediates essential events promoting prostate cancer development and acquisition of androgen independence. The GSK3 inhibitor lithium chloride and, more effectively, GSK3 gene silencing sensitized PC3 and DU145 prostate cancer cells to CDDO-Me cytotoxicity. These data suggest that modulation of GSK3β activation is involved in the cell death pathway engaged by CDDO-Me in prostate cancer cells. [Cancer Res 2008;68(17):6987–96]