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

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.

Cystic Fibrosis, CFTR, and Colorectal Cancer

“…CFTR is widely expressed in epithelial tissues, and as discussed above, CFTR influences epithelial cell homeostasis via a range of mechanisms, therefore it was not unexpected that CFTR dysregulation has been reported in a wide range of epithelial cancers. Upregulation of CFTR expression has been associated with several cancers such as gastric and ovarian cancers [123][124][125]. But for the great majority of cancer studies, loss of CFTR expression and/or activity is linked with cancer incidence, and in the majority of these reports, CFTR mutations or downregulation of CFTR expression in epithelial cancers is associated with rapid cancer growth, epithelial to mesenchymal transition (EMT), a reduction in cellular apoptosis, enhanced metabolic potential, and elevated patient morbidity and mortality.…”

Source of dopamine in gastric juice and luminal dopamine‐induced duodenal bicarbonate secretion via apical dopamine D2 receptors

“…Increasing evidence suggests that carbachol-and oestrogen-induced Ca 2+ -mediated DBS is mediated via the PI3K/Akt pathway (Tuo et al, 2012;Yang et al, 2017). In the present study, the calcium che- absorption (Walker et al, 2009).…”

“…Dopamine and quinpirole decreased the intracellular cAMP level in duodenal mucosa preparations, suggesting that the cAMP signalling pathway does not play a major role in dopamine‐induced DBS. Increasing evidence suggests that carbachol‐ and oestrogen‐induced Ca 2+ ‐mediated DBS is mediated via the PI3K/Akt pathway (Tuo et al, 2012; Yang et al, 2017). In the present study, the calcium chelator BAPTA‐AM completely blocked dopamine‐induced DBS in a real‐time pH titration experiment.…”

“…Dopamine is an important neurotransmitter and modulator in the gastrointestinal epithelium (Li et al, 2019; Yang et al, 2017). Patients with dopaminergic deficiency suffer from a higher incidence of peptic ulcers (Altschuler, 1996), whereas dopaminergic hyperfunction is associated with lower incidence of ulcers (Ozdemir et al, 2007).…”

Nicotine Induces Progressive Properties of Lung Adenocarcinoma A549 Cells by Inhibiting Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Expression and Plasma Membrane Localization

“… 21 Conversely, a high expression of CFTR was reported to correlate with progressive capacity in ovarian cancer cells 15 and Philadelphia chromosome-positive acute leukemia (Ph + ALL). 44 A knockdown of CFTR in ovarian cancer cells and Ph + ALL cells suppressed their metastatic capability, suggesting that CFTR played an oncogenic role in these 2 types of malignancies. Of interest, controversial functions of CFTR were reported in prostate cancer.…”