Abstract 194: The Golgi/ER protein p23/Tmp21 regulates PKCΔ-mediated apoptosis in prostate cancer cells

Protein kinase C isozymes have prominent and specific roles in the control of apoptosis and survival of cancer cells. Activation of PKCΔ in androgen-dependent prostate cancer cell models triggers an apoptotic response that is mediated by the release of death factors and the activation of the extrinsic apoptotic cascade. We have previously established that p23/Tmp21, a member of the p24 family ER/Golgi cargo protein, physically interacts with the C1 domains in PKC isozymes and regulates the their activation. Here we found that depletion of p23/Tmp21 significantly potentiates apoptosis induced by phorbol 12-myristate 13-acetate (PMA) in LNCaP prostate cancer cells and the DNA damaging agent doxorubicin. The potentiation of the PMA effect was prevented by the pan-PKC inhibitor GF 109203X or PKCΔ RNAi depletion. Yeast two-hybrid assay revealed that the PKCΔC1a-b domain interacts with p23/Tmp21. In addition, co-localization analysis by confocal microscopy demonstrated that GFP-PKCΔ C1b domain co-localizes with p23/Tmp21 in the perinuclear region. The interaction of PKCΔ and p23/Tmp21 in LNCaP cells was also confirmed by co-immunoprecipitation. Interestingly, disruption of PKCΔ-p23/Tmp21 association by depletion of p23/Tmp21 in LNCaP cells significantly accelerated PMA-induced PKCΔ translocation to the plasma membrane and potentiates the activation of PKCΔ downstream effectors ROCK and JNK. Moreover, a mutated PKCΔ that is unable to interact with p23/Tmp21 triggered significant apoptotic effect when expressed in LNCaP cells. In summary, our data provide evidence that p23/Tmp21 acts as an anchoring protein that retains PKCΔ at the perinuclear region, thus limiting its availability for signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 194. doi:10.1158/1538-7445.AM2011-194