Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance

International Journal of Molecular Sciences

Sol-Bi Shin¹  Chang-Hyeon Kim¹  Hay-Ran Jang¹  Hyungshin Yim¹ 

[1] Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Korea;

关键词: USP7;    PLK1;    taxane;    chemoresistance;    combination;   

DOI  :  10.3390/ijms21228629

来源: DOAJ

【 摘 要 】

USP7 is a promising target for the development of cancer treatments because of its high expression and the critical functions of its substrates in carcinogenesis of several different carcinomas. Here, we demonstrated the effectiveness of targeting USP7 in advanced malignant cells showing high levels of USP7, especially in taxane-resistant cancer. USP7 knockdown effectively induced cell death in several cancer cells of lung, prostate, and cervix. Depletion of USP7 induced multiple spindle pole formation in mitosis, and, consequently, resulted in mitotic catastrophe. When USP7 was blocked in the paclitaxel-resistant lung cancer NCI-H460^TXR cells, which has resistance to mitotic catastrophe, NCI-H460^TXR cells underwent apoptosis effectively. Furthermore, combination treatment with the mitotic kinase PLK1 inhibitor volasertib and the USP7 inhibitor P22077 showed a strong synergism through down-regulation of MDR1/ABCB1 in paclitaxel-resistant lung cancer. Therefore, we suggest USP7 is a promising target for cancer therapy, and combination therapy with inhibitors of PLK1 and USP7 may be valuable for treating paclitaxel-resistant cancers, because of their strong synergism.

【 授权许可】

Unknown