Suppression of GRP78 sensitizes human colorectal cancer cells to oxaliplatin by downregulation of CD24

Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum stress signaling regulator with anti-apoptotic properties. It has been demonstrated to promote tumor proliferation, survival and metastasis, and to confer resistance against a large variety of therapies. CD24 is a glycosyl-phosphatidylinositol-anchored protein, which is known to have a role in tumor progression, particularly in colorectal cancer (CRC). In the present study, oxaliplatin (L-OHP) was demonstrated to decrease the expression of CD24 in HT29 cells. Knockdown of CD24 using small interfering RNA resulted in sensitization of HT29 cells to L-OHP. By contrast, overexpression of CD24 rendered SW480 cells resistant to L-OHP, which indicated that CD24 antagonized L-OHP-induced cytotoxicity. A co-immunoprecipitation assay revealed that GRP78 physically associates with CD24. L-OHP suppresses the expression of GRP78 and CD24, in part come from the inhibition of interaction between the two. Suppression of GRP78 caused downregulation of CD24 expression and enhanced L-OHP-induced CD24 inhibition. Furthermore, down-regulation of GPR78 with a pharmacological inhibitor sensitized the CRC cells to L-OHP. Collectively, the present results indicate that CD24 antagonizes L-OHP-induced cytotoxicity and that GRP78 is involved in this process. A novel mechanism via which CRC cells acquire resistance to L-OHP was thereby revealed. Use of a combination of compounds which suppress GRP78 may help to improve the effectiveness of L-OHP in the treatment of CRC.