Oncotarget

Research Papers:

Doxorubicin induces apoptosis by targeting Madcam1 and AKT and inhibiting protein translation initiation in hepatocellular carcinoma cells

Jiayi Wang _, Lifang Ma, Xun Tang, Xiao Zhang, Yongxia Qiao, Yuling Shi, Yanfeng Xu, Zhongyong Wang, Yongchun Yu and Fenyong Sun

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Oncotarget. 2015; 6:24075-24091. https://doi.org/10.18632/oncotarget.4373

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Abstract

Jiayi Wang1,2,*, Lifang Ma1,*, Xun Tang1, Xiao Zhang1, Yongxia Qiao3, Yuling Shi4, Yanfeng Xu5, Zhongyong Wang6, Yongchun Yu7 and Fenyong Sun1

1 Department of Clinical Laboratory Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China

2 Translation Medicine of High Institute, Tongji University, Shanghai, China

3 School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China

4 Department of Dermatology, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China

5 Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine affiliated to Shanghai TCM University, Shanghai, China

6 Medical Examination Centre, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China

7 Shanghai Municipal Hospital of Traditional Chinese Medicine affiliated to Shanghai TCM University, Shanghai, China

* These authors have contributed equally to this study

Correspondence to:

Jiayi Wang, email:

Fenyong Sun, email:

Keywords: eIF4E, protein synthesis, caspase activity, 4EBP1, RNA-IP

Received: March 04, 2015 Accepted: May 30, 2015 Published: June 08, 2015

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.


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