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 PP2A complex inactivation and increased degradation of PP2A 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.
Highlights
The BCR-ABL oncogene causes chronic myelogenous leukemia(CML) and a fraction of pre-B cell acute lymphoblastic leukemias(pre-B-ALLs)
When normalized against the expression level in the normal human airway epithelial cell line HBE, CFTR expression in K562 and SUP-B15 cells was higher than in other leukemia cell lines (Figure 1A).CFTR expression in normal mononuclear cells (MNCs) was very low; among the 40 cases of ALL primary leukemia cells included in the study, the expression of CFTR was higher in the 20 cases of Philadelphia chromosome (Ph)+ B-ALL than in the 20 cases of Ph– B-ALL.in 12 cases of CML primary leukemic cells, the expression of CFTR in 6 cases of CML-blast crisis was higher than that in 6 cases of CML-chronic phase. These results demonstrated that CFTR protein is highly expressed in Ph+ acute leukemia cells (Figure 1C and Table 1)
CFTR expression is significantly higher in Ph+ acute leukemia cell lines and patient samples than in Ph– B-ALL and CML-chronic phase cells
Summary
The BCR-ABL oncogene causes chronic myelogenous leukemia(CML) and a fraction of pre-B cell acute lymphoblastic leukemias(pre-B-ALLs). The development of clinical resistance to tyrosine kinase inhibitors (TKIs) www.impactjournals.com/oncotarget has prompted investigators to seek novel compounds that target other signaling pathways that are essential for BCR-ABL-mediated cell survival. One mechanism by which a normal cell maintains the balance between tumor-inducing and tumor-suppressing signals as well as appropriate responses to extracellular stimuli is reversible protein phosphorylation [4]. A bona fide tumor suppressor protein, PP2A negatively regulates many of the signals triggered by oncogenic kinases. Likewise, impaired PP2A phosphatase activity has been linked to B-cell chronic lymphocytic leukemia(B-CLL), Ph+ B-ALL and CML-BC. PP2A has emerged as a highly promising drug target for the development of a new series of anticancer agents, which have the potential to overcome drug resistance induced in patients by continuous exposure to kinase inhibitor monotherapy
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