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Overexpression of RPS27a contributes to enhanced chemoresistance of CML cells to imatinib by the transactivated STAT3

2016; Impact Journals LLC; Volume: 7; Issue: 14 Linguagem: Inglês

10.18632/oncotarget.7888

1949-2553

Houcai Wang, Bingqian Xie, Yuanyuan Kong, Tao Yi, Guang Yang, Minjie Gao, Hongwei Xu, Fenghuang Zhan, Jumei Shi, Yiwen Zhang, Xiaosong Wu,

Acute Myeloid Leukemia Research

// Houcai Wang 1, * , Bingqian Xie 1, * , Yuanyuan Kong 1, * , Yi Tao 1 , Guang Yang 1 , Minjie Gao 1 , Hongwei Xu 2 , Fenghuang Zhan 2 , Jumei Shi 1 , Yiwen Zhang 1 , Xiaosong Wu 1 1 Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China 2 Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa, USA * These authors contributed equally to this work Correspondence to: Jumei Shi, e-mail: shijumei@tongji.edu.cn Yiwen Zhang, e-mail: ahzhyw@126.com Xiaosong Wu, e-mail: wux163@163.com Keywords: STAT3, RPS27a, imatinib, apoptosis, CML Received: November 11, 2015 Accepted: February 13, 2016 Published: March 03, 2016 ABSTRACT STAT3 plays a pivotal role in the hematopoietic system, which constitutively activated by BCR–ABL via JAK and Erk/MAP-kinase pathways. Phospho-STAT3 was overexpressed in imatinib-resistant CML patients as relative to imatinib responsive ones. By activation of the STAT3 pathway, BCR–ABL can promote cell cycling, and inhibit differentiation and apoptosis. Ribosomal protein S27a (RPS27a) performs extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. RPS27a can promote proliferation, regulate cell cycle progression and inhibit apoptosis of leukemia cells. However, the relationship between STAT3 and RPS27a has not been reported. In this study, we detected a significantly increased expression of STAT3 and RPS27a in bone marrow samples from CML-AP/BP patients compared with those from CML-CP. In addition, we also demonstrated that it was a positive correlation between the level of STAT3 and that of RPS27a. Imatinib-resistant K562/G01 cells expressed significantly higher levels of STAT3 and RPS27a compared with those of K562 cells. RPS27a could be transactivated by p-STAT3 through the specific p-STAT3-binding site located nt −633 to −625 and −486 to −478 of the RPS27a gene promoter in a dose-dependent manner. The transactivated RPS27a could decrease the percentage of apoptotic CML cells induced by imatinib. And the effect of STAT3 overexpression could be counteracted by the p-STAT3 inhibitor WP1066 or RPS27a knockdown. These results suggest that drugs targeting STAT3/p-STAT3/RPS27a combining with TKI might represent a novel therapy strategy in patients with TKI-resistant CML.