Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Immunology Programme, the Life Science Institute, National University of Singapore, Singapore, Singapore.
Nat Commun. 2021 Apr 16;12(1):2284. doi: 10.1038/s41467-021-22638-7.
Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.
耐药性是大多数人类肿瘤治疗的主要障碍。在这项研究中，我们发现双特异性磷酸酶 16（DUSP16）调节鼻咽癌、结直肠癌、胃癌和乳腺癌对化疗的耐药性。表达更高 DUSP16 的癌细胞比表达较低 DUSP16 的癌细胞对化疗诱导的细胞死亡具有内在的更高耐药性。在癌细胞中过表达 DUSP16 会导致在化疗治疗时增加对细胞死亡的抵抗力。相比之下，在癌细胞中敲低 DUSP16 会增加它们对治疗的敏感性。从机制上讲，DUSP16 抑制 JNK 和 p38 的激活，从而减少线粒体中 BAX 的积累以减少细胞凋亡。对头颈部癌症和乳腺癌患者队列中患者生存情况的分析支持 DUSP16 作为对化疗敏感性和治疗结果的标志物。因此，本研究将 DUSP16 鉴定为化疗疗效的预后标志物，以及克服癌症中化疗耐药性的治疗靶点。
