Gonzalez-Guerrico Anatilde M, Meshki John, Xiao Liqing, Benavides Fernando, Conti Claudio J, Kazanietz Marcelo G
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA.
J Biochem Mol Biol. 2005 Nov 30;38(6):639-45. doi: 10.5483/bmbrep.2005.38.6.639.
Protein kinase C (PKC) isozymes, a family of serine-threonine kinases, are important regulators of cell proliferation and malignant transformation. Phorbol esters, the prototype PKC activators, cause PKC translocation to the plasma membrane in prostate cancer cells, and trigger an apoptotic response. Studies in recent years have determined that each member of the PKC family exerts different effects on apoptotic or survival pathways. PKCdelta, one of the novel PKCs, is a key player of the apoptotic response via the activation of the p38 MAPK pathway. Studies using RNAi revealed that depletion of PKCdelta totally abolishes the apoptotic effect of the phorbol ester PMA. Activation of the classical PKCalpha promotes the dephosphorylation and inactivation of the survival kinase Akt. Studies have assigned a pro-survival role to PKCepsilon, but the function of this PKC isozyme remains controversial. Recently, it has been determined that the PKC apoptotic effect in androgen-dependent prostate cancer cells is mediated by the autocrine secretion of death factors. PKCdelta stimulates the release of TNFalpha from the plasma membrane, and blockade of TNFalpha secretion or TNFalpha receptors abrogates the apoptotic response of PMA. Molecular analysis indicates the requirement of the extrinsic apoptotic cascade via the activation of death receptors and caspase-8. Dissecting the pathways downstream of PKC isozymes represents a major challenge to understanding the molecular basis of phorbol ester-induced apoptosis.
蛋白激酶C（PKC）同工酶是丝氨酸 - 苏氨酸激酶家族，是细胞增殖和恶性转化的重要调节因子。佛波酯是PKC的原型激活剂，可导致PKC易位至前列腺癌细胞的质膜，并引发凋亡反应。近年来的研究表明，PKC家族的每个成员对凋亡或生存途径都有不同的影响。新型PKC之一的PKCδ是通过激活p38 MAPK途径引发凋亡反应的关键因子。使用RNAi的研究表明，PKCδ的缺失完全消除了佛波酯PMA的凋亡作用。经典PKCα的激活促进了生存激酶Akt的去磷酸化和失活。研究赋予了PKCε促生存作用，但其功能仍存在争议。最近，已确定雄激素依赖性前列腺癌细胞中的PKC凋亡作用是由死亡因子的自分泌介导的。PKCδ刺激肿瘤坏死因子α（TNFα）从质膜释放，阻断TNFα分泌或TNFα受体可消除PMA的凋亡反应。分子分析表明需要通过激活死亡受体和半胱天冬酶 - 8来启动外源性凋亡级联反应。剖析PKC同工酶下游的途径是理解佛波酯诱导凋亡分子基础的一项重大挑战。
