Stress granules affect the sensitivity of renal cancer cells to sorafenib by sequestering and stabilizing COX‑2 mRNA.

Abstract

Most patients with renal cancer will develop resistance to sorafenib therapy and will therefore exhibit disease progression. Effective therapies for these patients are extremely limited. Cyclooxygenase-2 (COX-2) promotes the malignant transformation of cancer cells and drug resistance. The potential of COX-2 inhibitor (celecoxib) administration in combination with sorafenib for the treatment of renal cancer is unclear. The present study demonstrated that sorafenib rapidly increased the expression of COX-2 in renal cancer cells, as determined using reverse transcription-quantitative PCR and western blotting. The results of the MTT assay and cell apoptosis experiment demonstrated that the cytotoxicity of sorafenib was also affected by COX-2 expression and celecoxib enhanced the cytotoxicity of sorafenib against renal cell carcinoma. Immunofluorescence analysis indicated that sorafenib induced the formation of stress granules (SGs) in renal cancer cells. In addition, COX-2 expression was associated with the formation of SGs, and SGs could capture and stabilize COX-2 mRNAs in renal cancer cells; this was confirmed using RNA fluorescence in situ hybridization and an actinomycin D chase experiment. The protective effect of SGs was further demonstrated in cell experiments and xenograft tumor models. Thus, the present study indicated that the use of celecoxib may significantly enhance the sensitivity of renal cancer cells to sorafenib and improve efficacy. Sorafenib-induced SGs may contribute to critical events that promote COX-2 expression and survival in renal cancer cells. Therefore, the present study may provide novel ideas for the treatment of renal cancer.