Oncotarget

Research Papers:

Suppression of esophageal tumor growth and chemoresistance by directly targeting the PI3K/AKT pathway

Bin Li, Jin Li, Wen Wen Xu, Xin Yuan Guan, Yan Ru Qin, Li Yi Zhang, Simon Law, Sai Wah Tsao and Annie L.M. Cheung _

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2014; 5:11576-11587. https://doi.org/10.18632/oncotarget.2596

Metrics: PDF 2335 views  |   HTML 1888 views  |   ?  


Abstract

Bin Li1,2,3, Jin Li1,7, Wen Wen Xu1,3, Xin Yuan Guan2,4, Yan Ru Qin5, Li Yi Zhang4, Simon Law2,6, Sai Wah Tsao1,2 and Annie L.M. Cheung1,2,3

1 Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China

2 Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China

3 The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), China

4 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China

5 Department of Clinical Oncology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China

6 Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China

7 Present Address: Research Center for Molecular Medicine of The Austrian Academy of Sciences, Vienna, Austria

Correspondence:

Annie L. M. Cheung, email:

Keywords: PI3K/AKT, targeted therapy, esophageal cancer, tumor growth, chemoresistance

Received: August 11, 2014 Accepted: October 18, 2014 Published: October 18, 2014

Abstract

Esophageal cancer is the sixth most common cause of cancer-related deaths worldwide. Novel therapeutic intervention is urgently needed for this deadly disease. The functional role of PI3K/AKT pathway in esophageal cancer is little known. In this study, our results from 49 pairs of human esophageal tumor and normal specimens demonstrated that AKT was constitutively active in the majority (75.5%) of esophageal tumors compared with corresponding normal tissues. Inhibition of the PI3K/AKT pathway with specific inhibitors, wortmannin and LY294002, significantly reduced Bcl-xL expression, induced caspase-3-dependent apoptosis, and repressed cell proliferation and tumor growth in vitro and in vivo without obvious toxic effects. Moreover, significantly higher expression level of p-AKT was observed in fluorouracil (5-FU)-resistant esophageal cancer cells. Inactivation of PI3K/AKT pathway markedly increased the sensitivity and even reversed acquired resistance of esophageal cancer cells to chemotherapeutic drugs in vitro. More importantly, the resistance of tumor xenografts derived from esophageal cancer cells with acquired 5-FU resistance to chemotherapeutic drugs was significantly abrogated by wortmannin treatment in animals. In summary, our data support PI3K/AKT as a valid therapeutic target and strongly suggest that PI3K/AKT inhibitors used in conjunction with conventional chemotherapy may be a potentially useful therapeutic strategy in treating esophageal cancer patients.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 2596