Inhibition of BMK1 pathway suppresses cancer stem cells through BNIP3 and BNIP3L

// Chengli Song 1, * , Qiang Xu 1, * , Kui Jiang 1 , Guangyu Zhou 1 , Xuebin Yu 1 , Lina Wang 1 , Yuting Zhu 1 , Liping Fang 1 , Zhe Yu 1 , Jiing-Dwan Lee 2 , Shi-Cang Yu 3 , Qingkai Yang 1 1 Department of Oncology, The Second Affiliated Hospital of DaLian Medical University, Institute of Cancer Stem Cell, DaLian Medical University, Dalian, Liaoning 116044, China 2 Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA 3 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China * These authors have contributed equally to this work Correspondence to: Qingkai Yang, e-mail: Yangqingkai@dlmedu.edu.cn Shi-cang Yu, e-mail: Yushicang@163.com Keywords: cancer stem cell, BMK1, kinase Received: May 29, 2015 Accepted: September 17, 2015 Published: September 29, 2015 ABSTRACT Cancer stem cells (CSCs) possess many characteristics associated with stem cells and are believed to drive tumor initiation. Although targeting of CSCs offers great promise for the new generation of therapeutics, lack of the effective drugable target and appropriate pharmacological reagents significantly impedes the development of chemotherapies. Here, we show that the phosphorylation of BMK1 was significantly correlated with not only embryonic and induced pluripotent stem (iPS) cells, but also the CSCs. It was showed that activation of BMK1 by the expression of MEK5D enhanced the self-renew (sphere formation), proliferation (clone formation) and tumorigenic capacity of CSCs. While BMK1 inhibitor, XMD8-92, suppressed these capacities. RNA-seq and microarray analysis revealed that inhibition of BMK1 significantly enhanced the expression of BNIP3 and BNIP3L, which play important roles in cell death. Further study indicated that shRNA-mediated knock down of BNIP3 and BNIP3L impairs the BMK1 inhibitor, XMD8-92-induced suppression of sphere formation and clone formation of CSC. Collectively, these results not only indicate that BMK1 plays an important role in maintaining “stemness” of CSCs, but also implicate that BMK1 might be a potential drug target for CSCs.