蛋白磷酸酶5的催化抑制剂通过破坏复合物II在肾癌中激活外源性凋亡途径。
Catalytic inhibitor of Protein Phosphatase 5 activates the extrinsic apoptotic pathway by disrupting complex II in kidney cancer.
发表日期：2023 Jul 14
作者：
Elham F Ahanin, Rebecca A Sager, Sarah J Backe, Diana M Dunn, Natela Dushukyan, Adam R Blanden, Nilamber A Mate, Tamie Suzuki, Tyler Anderson, Merin Roy, Jasmeen Oberoi, Chrisostomos Prodromou, Imad Nsouli, Michael Daneshvar, Gennady Bratslavsky, Mark R Woodford, Dimitra Bourboulia, John D Chisholm, Mehdi Mollapour
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
丝氨酸/苏氨酸蛋白磷酸酶-5（PP5）参与肿瘤进展和生存，使其成为一个有吸引力的治疗靶点。由于其保守的催化位点，特异性抑制蛋白磷酸酶一直是一个挑战。PP5在单一多肽链内包含其调控域，使其成为一个更理想的靶点。在这里，我们采用了一个基于计算机的方法来筛选和开发PP5的选择性抑制剂。化合物P053是PP5的一个竞争性抑制剂，它与其催化域结合并导致肾癌细胞凋亡。我们进一步证明了PP5与FADD、RIPK1和caspase 8相互作用，这些是外源性凋亡途径复合物II的组成部分。具体来说，PP5去磷酸化和失活死亡效应蛋白FADD，保持复合物II的完整性并调控外源性凋亡。我们的数据表明，PP5通过抑制外源性凋亡途径促进肾癌细胞生存。药理学上抑制PP5会激活这个途径，为治疗肾癌提供了可行的策略。版权所有 © 2023 Elsevier Ltd. 保留所有权利。
Serine/threonine protein phosphatase-5 (PP5) is involved in tumor progression and survival, making it an attractive therapeutic target. Specific inhibition of protein phosphatases has remained challenging because of their conserved catalytic sites. PP5 contains its regulatory domains within a single polypeptide chain, making it a more desirable target. Here we used an in silico approach to screen and develop a selective inhibitor of PP5. Compound P053 is a competitive inhibitor of PP5 that binds to its catalytic domain and causes apoptosis in renal cancer. We further demonstrated that PP5 interacts with FADD, RIPK1, and caspase 8, components of the extrinsic apoptotic pathway complex II. Specifically, PP5 dephosphorylates and inactivates the death effector protein FADD, preserving complex II integrity and regulating extrinsic apoptosis. Our data suggests that PP5 promotes renal cancer survival by suppressing the extrinsic apoptotic pathway. Pharmacologic inhibition of PP5 activates this pathway, presenting a viable therapeutic strategy for renal cancer.Copyright © 2023 Elsevier Ltd. All rights reserved.