Propofol Regulates ER Stress to Inhibit Tumour Growth and Sensitize Osteosarcoma to Doxorubicin

Abstract

Osteosarcoma is the most common malignant bone tumour affecting children and young adults. The antitumour role of propofol, a widely used intravenous sedative-hypnotic agent, has been recently reported in different cancer types. In this study, we aimed to assess the role of propofol on osteosarcoma and explore the possible mechanisms. Propofol of increasing concentrations (2.5, 5, 10, and 20 μg/ml) was used to treat the MG63 and 143B cells for 72 hours, and the CCK8 assay was applied to evaluate the tumour cell proliferation. Tumour cell migration and invasion were assessed with the transwell assay. The tumour cells were also treated with doxorubicin single agent or in combination with propofol to explore their synergic role. Differential expressed genes after propofol treatment were obtained and functionally assessed with bioinformatic tools. Expression of ER stress markers CHOP, p-eIF2α, and XBP1s was evaluated to validate the activation of ER stress response with western blot and qRT-PCR. The statistical analyses were performed with R v4.2.1. Propofol treatment led to significant growth inhibition in MG63 and 143B cells in a dose-dependent manner ( $p<0.05$ ). Osteosarcoma migration (MG63 91.4 (82–102) vs. 56.8 (49–65), $p<0.05$ ; 143B 96.6 (77–104) vs. 45.4 (28–54), $p<0.05$ ) and invasion (MG63 68.6 (61–80) vs. 32 (25–39), $p<0.05$ ; 143B 90.6 (72–100) vs. 39.2 (26–55), $p<0.05$ ) were reduced after propofol treatment. Doxorubicin sensitivity was increased after propofol treatment compared with the control group ( $p<0.05$ ). Bioinformatic analysis showed significant functional enrichment in ER stress response after propofol treatment. Upregulation of CHOP, p-eIF2α, and XBP1s was detected in MG63 and 143B secondary to propofol treatment. In conclusion, we found that propofol treatment suppressed osteosarcoma proliferation and invasion and had a synergic role with doxorubicin by inducing ER stress. Our findings provided a novel option in osteosarcoma therapy.