MKP-1 suppresses PARP-1 degradation to mediate cisplatin resistance

• Published in: Oncogene 2017-10, Vol.36 (43), p.5939-5947
• Main Authors: Wang, J, Kho, D H, Zhou, J-Y, Davis, R J, Wu, G S
• Format: Article
• Language: English
• Subjects: 42/89; 631/67/1059/2326; 82/80; 96/95; Apoptosis; c-Jun protein; Cancer therapies; Cell Biology; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Drug resistance; Drug Resistance, Neoplasm - genetics; Dual Specificity Phosphatase 1 - antagonists & inhibitors; Dual Specificity Phosphatase 1 - genetics; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Silencing - drug effects; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; JNK Mitogen-Activated Protein Kinases - genetics; JNK protein; Kinases; MAP kinase; MAP kinase phosphatase; Medicine; Medicine & Public Health; Oncology; original-article; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; PARP-1 protein; Patient outcomes; Phosphatases; Platinum; Platinum compounds; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Protein expression; Protein kinase; Proteins; Proteolysis - drug effects; Ribose; Transcription factors; Transferases; Ubiquitination
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.197

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.