Experimental Pharmacology Unit-Laboratory of Mercogliano (AV), Istituto Nazionale Tumori-IRCCS Fondazione G. Pascale, 80131 Naples, Italy.
Int J Mol Sci. 2021 Sep 21;22(18):10177. doi: 10.3390/ijms221810177.
Valosin-containing protein (VCP)/p97, a member of the AAA+ ATPase family, is a molecular chaperone recruited to the endoplasmic reticulum (ER) membrane by binding to membrane adapters (nuclear protein localization protein 4 (NPL4), p47 and ubiquitin regulatory X (UBX) domain-containing protein 1 (UBXD1)), where it is involved in ER-associated protein degradation (ERAD). However, VCP/p97 interacts with many cofactors to participate in different cellular processes that are critical for cancer cell survival and aggressiveness. Indeed, VCP/p97 is reported to be overexpressed in many cancer types and is considered a potential cancer biomarker and therapeutic target. This review summarizes the role of VCP/p97 in different cancers and the advances in the discovery of small-molecule inhibitors with therapeutic potential, focusing on the challenges associated with cancer-related VCP mutations in the mechanisms of resistance to inhibitors.
包含缬氨酸的蛋白 (VCP)/ p97，一种 AAA+ ATP 酶家族的成员，是一种分子伴侣，通过与膜衔接蛋白（核蛋白定位蛋白 4 (NPL4)、p47 和泛素调节 X (UBX) 结构域包含蛋白 1 (UBXD1)）结合被招募到内质网 (ER) 膜上，在那里它参与内质网相关蛋白降解 (ERAD)。然而，VCP/p97 与许多辅助因子相互作用，参与许多对癌细胞存活和侵袭性至关重要的细胞过程。事实上，VCP/p97 在许多癌症类型中表达过度，被认为是一种潜在的癌症生物标志物和治疗靶点。本综述总结了 VCP/p97 在不同癌症中的作用，以及发现具有治疗潜力的小分子抑制剂的进展，重点讨论了与癌症相关的 VCP 突变在抑制剂耐药机制中所带来的挑战。
