Autophagy inhibition enhances celecoxib-induced apoptosis in osteosarcoma

ABSTRACT

Osteosarcoma (OS) is the most prevalent bone malignancy in childhood and adolescence, with highly aggressive and early systemic metastases. Here, we reported that celecoxib, a selective COX-2 inhibitor in the NSAID class, exhibits strong antitumor activity in dose dependent manner in two OS cell lines-143B and U2OS. We showed that celecoxib inhibits OS cell growth, causes G0/G1-phase arrest, modulates apoptosis and autophagy and reduces migration in OS cells. In addition, the results of fluorescent mitochondrial probe JC-1 test indicated that the mitochondrial pathway mediates celecoxib-induced apoptosis. Significantly, the autophagy inhibitor CQ combined with celecoxib causes greater cell proliferation inhibition and apoptosis. Pharmacologic inhibition of autophagy with another potent autophagy inhibitor SAR405 also enhances celecoxib-mediated suppression of cell viability. These results were confirmed with shRNAs targeting the autophagy-related gene Atg5. In OS tumor xenografts in vivo, celecoxib also presents antitumor activity. Taken together, our results shed light on the function and mechanism of antitumor action of celecoxib for treatment of OS patients.

Keywords:

• Celecoxib
• apoptosis
• autophagy
• osteosarcoma

Disclosure statement

The authors declare no conflict of interest.

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Funding

This work was supported by the National Natural Science Foundation of China [81370600]; Innovation Program for Ph.D. students in Shanghai Jiaotong University School of Medicine [BXJ201731]; Innovation Program of Shanghai Municipal Education Commission [15ZZ056]; The Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning [TP2015022]; Shanghai Pujiang Program [15PJ1404800].