Abstract 129: Synthetic lethality induced by loss of PKC delta and mutated Ras

Table of Contents Synthetic Lethality Induced by Loss of PKC d and Mutated Ras Abstract Synthetic Lethality Induced by Loss of PKC δ and Mutated Ras Tongbo Zhu, * Lihua Chen, * Wei Du, Takanori Tsuji, and Changyan Chen Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston Abstract Synthetic lethal interaction between oncogenic Ha-ras and loss of PKC has been demonstrated. Recently, we reported that the concurrent knockdown of PKC α and β, via upregulating PKC δ, sensitizes cells with aberrant Ras signaling to apoptosis. As the continuation of the study, using the shRNA, we demonstrate that loss of PKC δ causes a lethal reaction in NIH3T3/Hras or prostate cancer DU145 cells that overexpress JNK. In this apoptotic process, PKC α and β are upregulated, and then associated with RACK1 (an adaptor for activated PKC) and JNK. Immunoblotting analysis shows that JNK is phosphorylated, accompanied with caspase 8 cleavage. The inhibition of JNK abrogates this apoptotic process triggered by PKC δ knockdown. Interestingly, without blocking PKC δ, the concurrent overexpression of wt- or CAT-PKCα and β is insufficient to induce apoptosis in the cells. Together with our previous findings, the data suggest that PKC α/β and δ function oppositely to maintain a balance that supports cells expressing v-ras to survive and prevents them from being eliminated through oncogenic stress-induced apoptosis. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 129.