MKP-1 suppresses PARP-1 degradation to mediate cisplatin resistance
Program in Molecular Medicine; Davis Lab; UMass Metabolic Network
Cancer Biology | Cellular and Molecular Physiology | Female Urogenital Diseases and Pregnancy Complications | Neoplasms
Understanding the mechanisms of platinum compound resistance, including cisplatin resistance, has important implications for improving cancer treatments. Previous studies identified a potential role for mitogen-activated protein kinase phosphatase-1 (MKP-1) in cisplatin resistance. This work focuses on the regulation of poly(ADP-ribose) polymerase-1 (PARP-1) expression by MKP-1. We found that MKP-1 overexpression stimulates PARP-1 and poly(ADP-ribose) (PAR) protein expression and cisplatin resistance while its downregulation suppresses PARP-1 and PAR protein expression and cisplatin resistance. Silencing MKP-1 promoted PARP-1 ubiquitination, which decreased PARP-1 protein levels. We also found that silencing c-Jun N-terminal kinase 1/2 (JNK1/2) decreased PARP-1 ubiquitination while increasing total PARP-1 protein levels. Furthermore, we showed that acquired cisplatin-resistant ovarian cancer cells expressed high levels of MKP-1 and PARP-1 proteins, and that silencing MKP-1 or PARP-1 increased cisplatin sensitivity in resistant cells. Notably, the pharmacologic inhibition of PARP activity restored cisplatin sensitivity in MKP-1 overexpressing cells. Thus, this work indicates that suppression of JNK1/2 activity by MKP-1 maintains PARP-1 levels and suggests that MKP-1-mediated cisplatin resistance can be bypassed by PARP-1 inhibition.
Cancer therapeutic resistance
DOI of Published Version
Oncogene. 2017 Oct 26;36(43):5939-5947. doi: 10.1038/onc.2017.197. Epub 2017 Jun 26. Link to article on publisher's site
Wang, J.; Kho, D. H.; Zhou, J-Y; Davis, Roger J.; and Wu, G. S., "MKP-1 suppresses PARP-1 degradation to mediate cisplatin resistance" (2017). Open Access Articles. 3280.