期刊
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
卷 37, 期 3, 页码 965-978出版社
KARGER
DOI: 10.1159/000430223
关键词
Potassium channel; Chronic lymphocytic leukemia; B-RAF; Mesenchymal stromal cell; Clofazimine
资金
- Italian Association for Cancer Research grant [11814, 15397]
- Progetti di Rilevante Interesse Nazionale grant of the Italian Ministry of Education and Research
- Young Investigator Grant of the University of Padova [GRIC12NN5G]
- Regione Veneto on chronic lymphocytic leukemia
Background/Aims: Pharmacological inhibition of the potassium channel Kv1.3 has been shown to selectively kill B cells from patients with chronic lymphocytic leukemia (B-CLL). Here we aimed to biophysically characterize and compare Kv1.3 channel activity in B cells isolated either from healthy subjects or patients and investigated the mechanism accounting for the increased protein expression in B-CLL cells. Methods: Kv1.3 activity was measured by patch clamp, while expression of the channel protein was assessed by Western blot and FACS analysis. B-CLL cells were co-cultured with mesenchymal stromal cells (MSC) and Kv1.3 inhibitor-induced apoptosis was assessed. Results: We demonstrate that Kv1.3 is highly expressed and is more active at resting membrane potential in human B-CLL cells than in healthy cells. Channel expression in pathologic cells decreased by the B-RAF kinase inhibitor PLX-4720, while it increased with Doxazosin, an alpha 1-adrenoceptor antagonist. Kv1.3 inhibitors induced death in B-CLL cells also when co-cultured with MSC. Conclusion: Our results contribute to the characterization of B-CLL cells, as it shows that upregulation of Kv1.3 in pathologic B lymphocytes is linked to the oncogenic B-RAF signalling. We also conclude that Kv1.3 inhibitors represent a valuable tool to induce apoptosis of B-CLL cells even in the presence of MSC. Copyright (C) 2015 S. Karger AG, Basel
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