Doxorubicin (Doxo) is one of the most widely used chemotherapeutic drugs for patients with hepatocellular carcinoma (HCC). Doxo is a DNA intercalating drug that inhibits topoisomerase II. Thereby Doxo has the ability to block DNA replication and induce apoptosis. However, the other targets and mechanisms through which Doxo induces apoptosis to treat HCC still remain unknown. Here, we identified Mucosal vascular addressin cell adhesion molecule 1 (Madcam1) as a potential Doxo target because Madcam1 overexpression suppressed, while Madcam1 depletion stimulated Doxo-induced apoptosis. Furthermore, we first revealed that Doxo can induce apoptosis by blocking protein translation initiation. In contrast, Madcam1 activated protein translation through an opposite mechanism. We also found de-phosphorylation of AKT may be an important pro-apoptotic event that is triggered by Doxo-induced Madcam1 down-regulation. Finally, we revealed that Madcam1 promoted increased AKT phosphorylation, which is essential for maintaining the sensitivity of HCC cells to Doxo treatment. Taken together, we uncovered a potential mechanism for Doxo-induced apoptosis in HCC treatment through targeting Madcam1 and AKT and blocking protein translation initiation.
[1]Tongji Univ, Dept Clin Lab Med, Shanghai Tenth Peoples Hosp, Shanghai 200092, Peoples R China.
[2]Tongji Univ, Translat Med High Inst, Shanghai 200092, Peoples R China.
[3]Shanghai Jiao Tong Univ, Sch Med, Sch Publ Hlth, Shanghai, Peoples R China.
[4]Tongji Univ, Shanghai Tenth Peoples Hosp, Dept Dermatol, Shanghai, Peoples R China.
[5]Shanghai TCM Univ, Shanghai Municipal Hosp Tradit Chinese Med, Dept Pharm, Shanghai, Peoples R China.
[6]Wenzhou Med Univ, Affiliated Hosp 1, Med Examinat Ctr, Wenzhou, Zhejiang, Peoples R China.
[7]Shanghai TCM Univ, Shanghai Municipal Hosp Tradit Chinese Med, Shanghai, Peoples R China.
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