High CFTR expression in Philadelphia chromosome-positive acute leukemia protects and maintains continuous activation of BCR-ABL and related signaling pathways in combination with PP2A
| Autor: | Huaqin Sun, Xi Yang, Duolan Naren, Wenming Xu, Tianyou Yan, Chunsen Wang, Xuehua Liu, Yuhuan Zheng, Yuping Gong |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Fusion Proteins bcr-abl Cystic Fibrosis Transmembrane Conductance Regulator 03 medical and health sciences 0302 clinical medicine Internal medicine hemic and lymphatic diseases medicine Humans Philadelphia Chromosome Protein Phosphatase 2 CFTR Acute leukemia Hematology biology business.industry Wnt signaling pathway Imatinib Protein phosphatase 2 respiratory system medicine.disease Molecular biology Cystic fibrosis transmembrane conductance regulator respiratory tract diseases PP2A Leukemia Myeloid Acute 030104 developmental biology Oncology 030220 oncology & carcinogenesis Immunology biology.protein business Ph+ acute leukemia Chronic myelogenous leukemia medicine.drug K562 cells Signal Transduction Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Xi Yang 1, * , Tianyou Yan 1, * , Yuping Gong 1 , Xuehua Liu 1 , Huaqin Sun 2 , Wenming Xu 2 , Chunsen Wang 3 , Duolan Naren 1 , Yuhuan Zheng 1 1 Department of Hematology, West China Hospital, Sichuan University, Chengdu, China 2 Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, China 3 Department of Hematology, Sichuan Provincial People’s Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, Chengdu, China * These authors contributed equally to this work Correspondence to: Yuping Gong, email: gongyuping2010@aliyun.com Keywords: CFTR, Ph + acute leukemia, PP2A Received: May 30, 2016 Accepted: February 06, 2017 Published: February 19, 2017 ABSTRACT Cystic fibrosis transmembrane conductance regulator (CFTR) is classified as an anion channel transporter of Cl − and HCO3 − . Through interactions with its PDZ domain, CFTR is capable of regulating other proteins, such as protein phosphatase 2A (PP2A). The aberrant expression and mutation of CFTR have been observed in several tumor, but not in philadelphia chromosome–positive(Ph + ) acute leukemia, including Ph + B cell acute lymphoblastic leukemia(Ph + B-ALL) and chronic myelogenous leukemia blast crisis phases (CML-BC). In this study, we demonstrated the mean expression level of CFTR in Ph + acute leukemia cells was markedly higher than that in Ph- B-ALL and CML-chronic phase cells. CFTRinh-172, a classic CFTR inhibitor, down-regulated the expression of CFTR, p-BCR-ABL and classical Wnt/β-catenin signaling in Ph + acute leukemia cells, while imatinib had no effect on CFTR. Importantly, reduced efficacy of CFTRinh-172 was closely associated with elevated PP2A phosphatase activity. Furthermore, we confirmed an interaction between CFTR and the PP2AA subunit in K562 cells. In addition, we demonstrated CFTR and PP2AA interact in the cytosol, resulting in PP2 A complex inactivation and increased degradation of PP2 A substrates via the lysosomal/proteasome pathway. In conclusion, our results showed CFTR was highly expressed in Ph + acute leukemia, which protected and maintained the continuous activation of BCR-ABL and the canonical Wnt/β-catenin signaling pathway by decreasing PP2A phosphatase activity. According to this working model of the CFTR-PP2A-BCR-ABL axis, targeting the CFTR protein will activate PP2A and may offer a new treatment strategy for Ph + acute leukemia, especially for patients exhibiting high levels of CFTR expression. |
| Databáze: | OpenAIRE |
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