Guo Jinjin, Zhu Tongbo, Chen Lihua, Nishioka Takashi, Tsuji Takanori, Xiao Zhi-Xiong J, Chen Chang Yan
Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Genes Cancer. 2010 Aug;1(8):836-46. doi: 10.1177/1947601910381645.
Although protein kinase C (PKC) plays an important role in sensitizing prostate cancer cells to apoptosis, and suppression of PKC is able to trigger an apoptotic crisis in cells harboring oncogenic ras, little is known about whether dyregulation of Ras effectors in prostate cancer cells, together with loss of PKC, is synthetically lethal. The current study aims at investigating whether prostate cancer cells with aberrant Ras effector signaling are sensitive to treatment with HMG (a PKC inhibitor) for the induction of apoptosis. We show that prostate cancer DU145 cells expressing a high level of JNK1 become susceptible to apoptosis after treatment with HMG, in which caspase 8 is activated and cytochrome c is released to the cytosol. In contrast, the addition of HMG sensitizes LNCaP or PC3 prostate cancer cells harboring an active Akt to apoptosis, in which ROS is upregulated to induce the UPR and GADD153 expression. The concurrent activation of JNK1 and Akt has an additive effect on apoptosis following PKC suppression. Thus, the data identify Akt and JNK1 as potential targets in prostate cancer cells for PKC inhibition-induced apoptosis.
尽管蛋白激酶C（PKC）在使前列腺癌细胞对凋亡敏感化方面发挥重要作用，并且抑制PKC能够在携带致癌性ras的细胞中引发凋亡危机，但对于前列腺癌细胞中Ras效应器的失调与PKC缺失是否具有合成致死性却知之甚少。当前研究旨在调查具有异常Ras效应器信号传导的前列腺癌细胞是否对用HMG（一种PKC抑制剂）诱导凋亡的治疗敏感。我们发现，表达高水平JNK1的前列腺癌DU145细胞在用HMG处理后变得易于凋亡，其中半胱天冬酶8被激活且细胞色素c释放到细胞质中。相反，添加HMG使具有活性Akt的LNCaP或PC3前列腺癌细胞对凋亡敏感，其中活性氧上调以诱导未折叠蛋白反应和GADD153表达。JNK1和Akt的同时激活对PKC抑制后的凋亡具有累加效应。因此，这些数据确定Akt和JNK1是前列腺癌细胞中PKC抑制诱导凋亡的潜在靶点。
