Circadian Clock Protein PERIOD2 Suppresses the PI3K/Akt Pathway and Promotes Cisplatin Sensitivity in Ovarian Cancer

BACKGROUND: The mortality rate of ovarian cancer is the highest among gynecological tumors. The two factors leading to high mortality of ovarian cancer are late clinical stage and chemotherapy resistance. It is very important to reverse or intervene chemotherapy resistance. Abnormal circadian rhythm is related to the occurrence of tumor, and circadian clock protein PERIOD2 (PER2) acts as a tumor suppressor in cancer; however, little is known about its involvement in chemosensitivity. METHODS: This study aimed to investigate the role and underlying mechanisms of PER2 in ovarian cancer sensitivity to cisplatin. Overexpression and knockdown of PER2 were performed to explore its role in ovarian cancer cell sensitivity to cisplatin both in vitro and in vivo. The protein levels of PI3K, AKT, caspase 3, E-cadherin, and other drug resistance-related molecules were determined in parental SKOV3 and SKOV3/DDP cells as well as in xenograft tumor tissues. RESULTS: Compared with parental cells, SKOV3/DDP cells had dramatically decreased PER2 expression, possibly due to hypermethylation in the PER2 promoter. PER2 overexpression significantly inhibited proliferation while promoting cisplatin-induced apoptosis in SKOV3 and SKOV3/DDP cells. In agreement, PER2-overexpressing SKOV3/DPP cells yielded significantly reduced tumor mass in cisplatin-treated mice compared with control cells. Mechanistically, PER2 overexpression remarkably reduced the protein amounts of PI3K, AKT, and MDR1 while increasing those of caspase 3 and E-cadherin in tumor tissues. Knockdown of PER2 exhibited opposite effects. PER2 overexpression also reduced the serum levels of TNF-α and IL-6 in tumor-bearing mice before the initiation of cisplatin treatment. CONCLUSION: This study suggests that loss of PER2 contributes to cisplatin resistance in SKOV3 cells, possibly by activating the PI3K/AKT pathway and EMT, inhibiting apoptosis, and promoting drug efflux and inflammatory responses. Overexpression of PER2 could reverse these alterations and sensitize both parental SKOV3 and SKOV3/DDP cells to cisplatin.