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: Jiayi Wang, Lifang Ma, Xun Tang, Xiao Zhang, Yongxia Qiao, Yuling Shi, Yanfeng Xu, Zhongyong Wang, Yongchun Yu, Fenyong Sun
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 27 Pg. 24075-91 (Sep 15 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26124182 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antibiotics, Antineoplastic
• Cell Adhesion Molecules
• Cell Cycle Proteins
• EIF4EBP1 protein, human
• Eukaryotic Initiation Factor-4E
• Immunoglobulins
• MADCAM1 protein, human
• Mucoproteins
• Phosphoproteins
• RNA
• Doxorubicin
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt
• Caspases

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Antibiotics, Antineoplastic (chemistry)
• Apoptosis
• Carcinoma, Hepatocellular (metabolism)
• Caspases (metabolism)
• Cell Adhesion Molecules
• Cell Cycle Proteins
• Cell Line, Tumor
• Cell Proliferation
• DNA Replication
• Doxorubicin (chemistry)
• Eukaryotic Initiation Factor-4E (metabolism)
• Humans
• Immunoglobulins (metabolism)
• Immunoprecipitation
• Liver Neoplasms (metabolism)
• Mice
• Mice, Nude
• Mucoproteins (metabolism)
• Neoplasm Transplantation
• Phosphoproteins (metabolism)
• Phosphorylation
• Protein Transport
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA (chemistry)