title: Doxorubicin induces apoptosis by targeting Madcam1 and AKT and inhibiting protein translation initiation in hepatocellular carcinoma cells.
abstract: 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.
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.|Translation Medicine of High Institute, Tongji University, Shanghai, China.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Dermatology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine affiliated to Shanghai TCM University, Shanghai, China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Medical Examination Centre, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
authors.forename: Zhongyong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Shanghai Municipal Hospital of Traditional Chinese Medicine affiliated to Shanghai TCM University, Shanghai, China.
authors.forename: Yongchun
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Fenyong
authors.initials: F
authors.lastname: Sun
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004261:DNA Replication; D004317:Doxorubicin / Q000737:chemistry*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009088:Mucoproteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012313:RNA / Q000737:chemistry
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D007136:Immunoglobulins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D010750:Phosphoproteins; D012313:RNA; D004317:Doxorubicin; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases
keywords: 4EBP1; RNA-IP; caspase activity; eIF4E; protein synthesis