@article {von Burstin325, author = {Vivian A. von Burstin and Liqing Xiao and Marcelo G. Kazanietz}, title = {Bryostatin 1 Inhibits Phorbol Ester-Induced Apoptosis in Prostate Cancer Cells by Differentially Modulating Protein Kinase C (PKC) δ Translocation and Preventing PKCδ-Mediated Release of Tumor Necrosis Factor-α}, volume = {78}, number = {3}, pages = {325--332}, year = {2010}, doi = {10.1124/mol.110.064741}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Bryostatin 1, a macrocyclic lactone that has been widely characterized as an ultrapotent protein kinase C (PKC) activator, displays marked pharmacological differences with the typical phorbol ester tumor promoters. Bryostatin 1 impairs phorbol 12-myristate 13-acetate (PMA)-induced tumor promotion in mice and is in clinical trials as an anticancer agent for a number of hematopoietic malignancies and solid tumors. In this study, we characterized the effect of bryostatin 1 on LNCaP prostate cancer cells, a cellular model in which PKC isozymes play important roles in the control of growth and survival. Although phorbol esters promote a strong apoptotic response in LNCaP cells via PKCδ-mediated release of TNFα, bryostatin 1 failed to trigger a death effect even at high concentrations, and it prevented PMA-induced apoptosis in these cells. Mechanistic analysis revealed that bryostatin 1 is unable to induce TNFα release, and it impairs the secretion of this cytokine from LNCaP cells in response to PMA. Unlike PMA, bryostatin 1 failed to promote the translocation of PKCδ to the plasma membrane. Moreover, bryostatin 1 prevented PMA-induced PKCδ peripheral translocation. Studies using a membrane-targeted PKCδ construct revealed that the peripheral localization of the kinase is a requisite for triggering apoptosis in LNCaP cells, arguing that mislocalization of PKCδ may explain the actions of bryostatin 1. The identification of an antiapoptotic effect of bryostatin 1 may have significant relevance in the context of its therapeutic efficacy.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/78/3/325}, eprint = {https://molpharm.aspetjournals.org/content/78/3/325.full.pdf}, journal = {Molecular Pharmacology} }