Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Cell Chem Biol. 2022 Mar 17;29(3):517-529.e5. doi: 10.1016/j.chembiol.2021.11.005. Epub 2021 Nov 29.
Targeting protein quality control (PQC) pathways using proteasome or p97/VCP inhibition can effectively treat blood tumors. However, in solid tumors, only p97/VCP inhibitors are effective. To probe this difference in efficacy, we tracked HCT116 colon cancer cells using temporal proteomics to define the cellular and molecular responses to proteasome and p97 inhibition. Proteins involved in general PQC pathways were similarly upregulated by both treatments, suggesting that the proteotoxic stress caused by inhibitors does not explain the differential therapeutic effectiveness. Unexpectedly, proteins specifically dysregulated by two p97 inhibitors are involved in cell cycle control. Indeed, eleven cell cycle proteins were downregulated by p97 inhibition but not by proteasome inhibition. Western blot analysis validated the degradation of cyclin D1 and Securin, which depends on proteasome but not on p97. Differing regulation of cell cycle proteins by p97 and the proteasome may, therefore, explain the therapeutic efficacy of p97 inhibitors in colon cancer.
靶向蛋白质质量控制 (PQC) 途径的蛋白酶体或 p97/VCP 抑制可以有效治疗血液肿瘤。然而，在实体肿瘤中，只有 p97/VCP 抑制剂有效。为了探究这种疗效差异，我们使用时间蛋白质组学跟踪 HCT116 结肠癌细胞，以定义对蛋白酶体和 p97 抑制的细胞和分子反应。两种治疗方法均上调了参与一般 PQC 途径的蛋白质，表明抑制剂引起的蛋白毒性应激并不能解释治疗效果的差异。出乎意料的是，两种 p97 抑制剂特异性失调的蛋白质参与细胞周期控制。事实上，有 11 种细胞周期蛋白被 p97 抑制而不是蛋白酶体抑制下调。Western blot 分析验证了细胞周期蛋白 D1 和 Securin 的降解，这依赖于蛋白酶体而不是 p97。因此，p97 和蛋白酶体对细胞周期蛋白的不同调节可能解释了 p97 抑制剂在结肠癌中的治疗效果。
