Stromal cells attenuate the cytotoxicity of imatinib on Philadelphia chromosome-positive leukemia cells by up-regulating the VE-cadherin/β-catenin signal.

Abstract

β-Catenin is a key regulator of leukemia stem cell maintenance and drug resistance. Herein, we investigated the protective effects of the stromal cell-mediated VE-cadherin-β-catenin signal on Ph+ leukemia cells during imatinib treatment. We found stromal cells could desensitize imatinib and up-regulate VE-cadherin expression on Ph+ leukemia cells (K562 and SUP-B15 cells), which further stabilized and activated β-catenin. Knockdown of VE-cadherin with shRNA diminished the β-catenin protein and partly resensitized Ph+ leukemia cells to imatinib despite the presence of stromal cells, suggesting VE-cadherin is a potential target in the treatment of Ph+ leukemia.

• Authors: Chong Chen, Huan-Xin Zhang, Man Wang, Xu-Guang Song, Jiang Cao, Lin Wang, Jian-Lin Qiao, Xiao-Yun Lu, Zheng-Xiang Han, Ping Zhu, Bin Pan, Qing-Yun Wu, Kai Zhao, Zhi-Ling Yan, Zhen-Yu Li, Ling-Yu Zeng, Kai-Lin Xu
• Journal: Leukemia research (Leuk Res) Vol. 38 Issue 12 Pg. 1460-8 (Dec 2014) ISSN: 1873-5835 [Electronic] England
• PMID: 25443888 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antigens, CD
• Antineoplastic Agents
• Benzamides
• Cadherins
• Neoplasm Proteins
• Piperazines
• Pyrimidines
• beta Catenin
• cadherin 5
• Imatinib Mesylate

Topics

• Antigens, CD (biosynthesis)
• Antineoplastic Agents (pharmacology)
• Benzamides (pharmacology)
• Cadherins (biosynthesis)
• Cell Line, Tumor
• Coculture Techniques
• Drug Resistance, Neoplasm (drug effects)
• Gene Expression Regulation, Leukemic (drug effects)
• Humans
• Imatinib Mesylate
• K562 Cells
• Leukemia (drug therapy, metabolism, pathology)
• Neoplasm Proteins (biosynthesis)
• Philadelphia Chromosome
• Piperazines (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction (drug effects)
• Stromal Cells (metabolism, pathology)
• Up-Regulation (drug effects)
• beta Catenin (biosynthesis)