Ruvolo Vivian R, Karanjeet Kul B, Schuster Todd F, Brown Rhoderick, Deng Yibin, Hinchcliffe Edward, Ruvolo Peter P
Section of Signal Transduction and Apoptosis, Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
J Signal Transduct. 2010 Jan 1;2010:584657. doi: 10.1155/2010/584657.
The synthetic Vitamin A analog fenretinide is a promising chemotherapeutic agent. In the current paper, the role of PKC δ was examined in fenretinide-induced apoptosis in lymphoid leukemia cells. Levels of proapoptotic cleaved PKC δ positively correlated with drug sensitivity. Fenretinide promoted reactive oxygen species (ROS) generation. The antioxidant Vitamin C prevented fenretinide-induced PKC δ cleavage and protected cells from fenretinide. Suppression of PKC δ expression by shRNA sensitized cells to fenretinide-induced apoptosis possibly by a mechanism involving ROS production. A previous study demonstrated that fenretinide promotes degradation of antiapoptotic MCL-1 in ALL cells via JNK. Now we have found that fenretinide-induced MCL-1 degradation may involve PKC δ as cleavage of the kinase correlated with loss of MCL-1 even in cells when JNK was not activated. These results suggest that PKC δ may play a complex role in fenretinide-induced apoptosis and may be targeted in antileukemia strategies that utilize fenretinide.
合成维生素A类似物芬维A胺是一种很有前景的化疗药物。在当前论文中，研究了蛋白激酶Cδ（PKCδ）在芬维A胺诱导淋巴细胞白血病细胞凋亡中的作用。促凋亡的裂解型PKCδ水平与药物敏感性呈正相关。芬维A胺促进活性氧（ROS）生成。抗氧化剂维生素C可阻止芬维A胺诱导的PKCδ裂解，并保护细胞免受芬维A胺的影响。通过短发夹RNA（shRNA）抑制PKCδ表达可使细胞对芬维A胺诱导的凋亡敏感，其机制可能涉及ROS产生。先前的一项研究表明，芬维A胺通过JNK促进急性淋巴细胞白血病（ALL）细胞中抗凋亡蛋白MCL-1的降解。现在我们发现，芬维A胺诱导的MCL-1降解可能涉及PKCδ，因为即使在JNK未激活的细胞中，该激酶的裂解也与MCL-1的丧失相关。这些结果表明，PKCδ可能在芬维A胺诱导的凋亡中发挥复杂作用，并且可能成为利用芬维A胺的抗白血病策略的靶点。
