PKC and the Regulation of Apoptotic Responses in Prostate Carcinogenesis
Unlike most cell types, androgen-dependent prostate cancer cells undergo apoptosis in response to phorbol esters through the activation of discrete PKC isozymes. A main goal in our laboratory is to elucidate the signaling mechanisms underlying this apoptotic effect using both molecular and pharmacological strategies. The use of adenoviral delivery of active and inactive PKCs proved to be a highly efficient approach to determine which PKC isozymes mediate the apoptotic response. A key question is how each individual member of the PKC family regulates apoptotic and anti-apoptotic signaling pathways in prostate cancer cells. Strong candidates include the MAPK cascades and the PI3K/Akt pathways, which play crucial roles in malignant transformation and survival in prostate carcinogenesis and other cancer models. Other major projects focus on the regulation of PKC signaling by androgens in vitro and in vivo. The development of transgenic mice for PKC isozymes will be critical to understand the functions of PKCs in normal prostate function and prostate carcinogenesis.
- Phorbol ester-induced apoptosis in prostate cancer cells.
- PKCalpha and PKCdelta as pro-apoptotic PKC isozymes in prostate cancer cells.
- Translocation of PKC isozymes in prostate cancer cells.
- Regulation of signaling pathways by PKC isozymes in prostate cancer cells.
- Transcriptional regulation of PKC isozymes in prostate cells.
Representative papers (PubMed)
- Fujii, T., Garcia-Bermejo, M.L., Bernabo, J.L., Caamano, J., Ohba, M., Kuroki, T., Li, L., Yuspa, S.H., and Kazanietz, M.G. Involvement of PKC in phorbol ester-induced apoptosis in LNCaP prostate cancer cells. Lack of proteolytic cleavage of PKCdelta. J. Biol. Chem. 275: 7574-7582 (2000). [ html ] [ pdf ]
- Garcia-Bermejo, M.L., Coluccio Leskow, F., Fujii, T., Wang, Q., Blumberg, P.M., Ohba, M., Kuroki, T., Han, K-C., Lee, J., Marquez, V.E., and Kazanietz, M.G. DAG-lactones, a new class of PKC agonists, induce apoptosis in LNCaP prostate cancer cells by selective activation of PKCa. J. Biol. Chem. 277: 645-655 (2002). [ html ] [ pdf ]
- Eroles, P., Wang, H., Coluccio-Leskow, F., Fernandez, N., Tanaka, Y., Gavrielides, M.V., Fujii, T., and Kazanietz, M.G. Protein kinase C and phorbol ester receptors in prostate carcinogenesis. In "Recent Research Developments in Endocrinology" 2: 237-250 (2001).