Cooke Mariana, Magimaidas Andrew, Casado-Medrano Victoria, Kazanietz Marcelo G
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Mol Carcinog. 2017 Jun;56(6):1531-1542. doi: 10.1002/mc.22617. Epub 2017 Mar 10.
Few kinases have been studied as extensively as protein kinase C (PKC), particularly in the context of cancer. As major cellular targets for the phorbol ester tumor promoters and diacylglycerol (DAG), a second messenger generated by stimulation of membrane receptors, PKC isozymes play major roles in the control of signaling pathways associated with proliferation, migration, invasion, tumorigenesis, and metastasis. However, despite decades of research, fundamental questions remain to be answered or are the subject of intense controversy. Primary among these unresolved issues are the role of PKC isozymes as either tumor promoter or tumor suppressor kinases and the incomplete understanding on isozyme-specific substrates and effectors. The involvement of PKC isozymes in cancer progression needs to be reassessed in the context of specific oncogenic and tumor suppressing alterations. In addition, there are still major hurdles in addressing isozyme-specific function due to the limited specificity of most pharmacological PKC modulators and the lack of validated predictive biomarkers for response, which impacts the translation of these agents to the clinic. In this review we focus on key controversial issues and upcoming challenges, with the expectation that understanding the intricacies of PKC function will help fulfill the yet unsuccessful promise of targeting PKCs for cancer therapeutics.
很少有激酶像蛋白激酶C（PKC）那样得到广泛研究，尤其是在癌症背景下。作为佛波酯肿瘤启动子和二酰基甘油（DAG，一种由膜受体刺激产生的第二信使）的主要细胞靶点，PKC同工酶在控制与增殖、迁移、侵袭、肿瘤发生和转移相关的信号通路中发挥着重要作用。然而，尽管经过了数十年的研究，一些基本问题仍有待解答，或者仍是激烈争论的主题。这些未解决问题中首要的是PKC同工酶作为肿瘤启动子激酶还是肿瘤抑制激酶的作用，以及对同工酶特异性底物和效应器的不完全理解。PKC同工酶在癌症进展中的作用需要在特定致癌和抑癌改变的背景下重新评估。此外，由于大多数药理学PKC调节剂的特异性有限，以及缺乏经过验证的反应预测生物标志物，在解决同工酶特异性功能方面仍然存在重大障碍，这影响了这些药物向临床的转化。在本综述中，我们关注关键的争议问题和即将到来的挑战，期望理解PKC功能的复杂性将有助于实现尚未成功的将PKC作为癌症治疗靶点的承诺。
