Halder Kuntal, Banerjee Sayantan, Bose Anamika, Majumder Saikat, Majumdar Subrata
Division of Molecular Medicine, Bose Institute, Kolkata, India.
PLoS One. 2014 Mar 14;9(3):e91656. doi: 10.1371/journal.pone.0091656. eCollection 2014.
In the present study, we observed a marked variation in the expression of PKCα and PKCδ isotypes in B16F10 melanoma tumor cells compared to the normal melanocytes. Interestingly, the tumor instructed expression or genetically manipulated overexpression of PKCα isotype resulted in enhanced G1 to S transition. This in turn promoted cellular proliferation by activating PLD1 expression and subsequent AKT phosphorylation, which eventually resulted in suppressed ceramide generation and apoptosis. On the other hand, B16F10 melanoma tumors preferentially blocked the expression of PKCδ isotype, which otherwise could exhibit antagonistic effects on PKCα-PLD1-AKT signaling and rendered B16F10 cells more sensitive to apoptosis via generating ceramide and subsequently triggering caspase pathway. Hence our data suggested a reciprocal PKC signaling operational in B16F10 melanoma cells, which regulates ceramide generation and provide important clues to target melanoma cancer by manipulating the PKCδ-ceramide axis.
在本研究中，我们观察到与正常黑素细胞相比，B16F10黑色素瘤肿瘤细胞中PKCα和PKCδ同种型的表达存在显著差异。有趣的是，PKCα同种型的肿瘤诱导表达或基因操作过表达导致G1期到S期的转换增强。这反过来通过激活PLD1表达和随后的AKT磷酸化促进细胞增殖，最终导致神经酰胺生成和凋亡受到抑制。另一方面，B16F10黑色素瘤肿瘤优先阻断PKCδ同种型的表达，否则其可能对PKCα-PLD1-AKT信号传导表现出拮抗作用，并通过生成神经酰胺并随后触发半胱天冬酶途径使B16F10细胞对凋亡更敏感。因此，我们的数据表明在B16F10黑色素瘤细胞中存在相互的PKC信号传导，其调节神经酰胺生成，并为通过操纵PKCδ-神经酰胺轴靶向黑色素瘤癌症提供重要线索。
