Period circadian regulator 2 suppresses drug resistance to cisplatin by PI3K/AKT pathway and improves chronochemotherapeutic efficacy in cervical cancer

Abstract

Objective: Chronotherapy, a promising therapy, may build up the chemotherapy efficacy through thinking about timing of therapy. Here, we observed the roles of period circadian regulator 2 (PER2) on cervical cancer progression and the therapeutic efficacy of cisplatin (DDP) based on the circadian rhythm of PER2.

Methods: When Hela/DDP and SiHa/DDP transfected with pcDNA3.1-PER2 and/or treated with human epidermal growth factor (hEGF), viability, apoptosis, migration, and nuclear translocation of NF-κB p65 were detected by CCK-8, flow cytometry, transwell, immunofluorescence and western blot. Furthermore, the expression of circadian rhythm regulators, multidrug resistance, and epithelial-mesenchymal transition (EMT) proteins was detected by western blot. Hela/DDP cells-induced tumor formation in nude mice was constructed. The expression of PER2 was measured at different time point by RT-qPCR. Cisplatin was separately injected into mice with cervical cancer at the highest and lowest expression of PER2. After 5 weeks, tumor volume was measured and tumor proliferation was assessed by immunohistochemistry.

Results: Overexpression of PER2 significantly reduced proliferative and migrated capacities and nuclear translocation of NF-κB p65 as well as enhanced apoptosis in Hela/DDP and SiHa/DDP cells. Meanwhile, its overexpression elevated the expression of circadian rhythm regulators as well as lowered the expression of multidrug resistance proteins and EMT pathway activation by suppressing PI3K/AKT pathway. PER2 was rhythmically expressed in cervical cancer tissues. Compared to cisplatin treatment at the lowest expression of PER2, tumor growth and proliferation of tumor cells were distinctly suppressed in mice treated with cisplatin at the highest expression of PER2.

Conclusion: Our findings confirmed the circadian rhythm of PER2 in cervical cancer and its overexpression restrained the resistance to cisplatin in cervical cancer by PI3K/AKT pathway. It may improve cisplatin efficacy through considering the circadian rhythm of PER2.

Keywords: Cervical cancer; Circadian rhythm; Cisplatin; Drug resistance; PER2; PI3K/AKT pathway.