Ion channels and anti-cancer immunity

Panyi, György; Beeton, Christine; Felipe, Antônio

doi:10.1098/rstb.2013.0106

Cited by 50 publications

(29 citation statements)

References 89 publications

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“…Targeting KCa1.1 is unlikely to lead to immunosuppression, since most immune cells do not express this channel. We and others have extensively assessed human and rat T, B, and natural killer lymphocytes via patchclamp electrophysiology, and these cells do not express KCa1.1 channels (13,28,30,34,40,41). Neutrophils and eosinophils do not either (30,42,43).…”

Section: Discussionmentioning

confidence: 99%

KCa1.1 Inhibition Attenuates Fibroblast‐like Synoviocyte Invasiveness and Ameliorates Disease in Rat Models of Rheumatoid Arthritis

Tanner

Huq

et al. 2014

Arthritis & Rheumatology

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Objective Fibroblast-like synoviocytes (FLS) participate in joint inflammation and damage during rheumatoid arthritis (RA) and its animal models. The purpose of this study was to define the importance of KCa1.1 (BK, Maxi-K, Slo1, KCNMA1) channel expression and function in FLS and to establish these channels as potential new targets for RA therapy. Methods We compared KCa1.1 expression levels in FLS from rats with the pristane-induced arthritis (PIA) model of RA and in FLS from healthy rats. We then used ex vivo functional assays combined with siRNA-induced knock-down, over-expression, and functional modulation of KCa1.1 in PIA-FLS. Finally, we determined the effectiveness of modulating KCa1.1 in two rat models of RA, moderate PIA and severe complete Freund’s adjuvant collagen-induced arthritis (CFA-CIA). Results We found that PIA-FLS express the KCa1.1 channel as their major potassium channel, as do FLS from patients with RA. In contrast, FLS from healthy rats expressed fewer of these channels. Inhibiting the function or expression of KCa1.1 ex vivo reduced the proliferation, production of proteases, and invasive properties of PIA-FLS whereas opening native KCa1.1 or over-expressing the channel enhanced the invasiveness of both PIA-FLS and FLS isolated from healthy rats. Treatment with a KCa1.1 channel blocker starting at onset of clinical signs stopped disease progression in both PIA and CFA-CIA, reduced joint and bone damage, and inhibited FLS invasiveness and proliferation. Conclusion Our results demonstrate a critical role for KCa1.1 channels in the regulation of FLS invasiveness and suggest they represent a potential therapeutic target for RA.

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Section: Discussionmentioning

confidence: 99%

KCa1.1 Inhibition Attenuates Fibroblast‐like Synoviocyte Invasiveness and Ameliorates Disease in Rat Models of Rheumatoid Arthritis

Tanner

Huq

et al. 2014

Arthritis & Rheumatology

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“…All subsets tested (T, B and regulatory and NK lymphocytes) expressed Kv1.3 and KCa3.1 channels, but BK channels were never identified in these cells [154, 155,156]. Thus, BK channels only seem to play a role in myeloid cells.…”

Section: Do Bk Channels Play a Role Within Immune Cells?mentioning

confidence: 99%

Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy

Hoa

Wilson

et al. 2014

International Immunopharmacology

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The Big Potassium (BK) ion channel is commonly known by a variety of names (Maxi-K, KCNMA1, slo, Stretch-activated potassium channels, KCa1.1). Each name reflects a different physical property displayed by this single ion channel. This transmembrane channel is found on nearly every cell type of the body and has its own distinctive roles for that tissue type. The BKα channel contains the pore that releases potassium ions from intracellular stores. This ion channel is found on the cell membrane, endoplasmic reticulum, Golgi and mitochondria. Complex splicing pathways produce different isoforms. The BKα channels can be phosphorylated, palmitoylated and myristylated. BK is composed of a homo-tetramer that interacts with β and γ chains. These accessory proteins provide a further modulating effect on the functions of BKα channels. BK channels play important roles in cell division and migration. In this review, we will focus on the biology of BK channels, especially its role, and that it has in the immune response towards cancer. Recent proteomic studies have linked BK channels with various proteins. Some of these interactions offer further insight into the role that BK channels have with cancers, especially with brain tumors. This review shows that BK channels have a complex interplay with intracellular components of cancer cells and still have plenty of secrets to be discovered.

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“…13, 14, 15 To understand the molecular events that lead to delayed myotube fusion, we assessed the role of potassium channels in regulating proliferation, matrix metalloproteinase (MMP) levels, migration, and fusion of skeletal myoblasts from patients with DM1 and from healthy volunteers. We show that the voltage- and calcium-activated potassium channel, KCa1.1 is a crucial regulator of myoblasts proliferation and fusion.…”

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Functional KCa1.1 channels are crucial for regulating the proliferation, migration and differentiation of human primary skeletal myoblasts

Tajhya

Tanner

et al. 2016

Cell Death Dis

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Myoblasts are mononucleated precursors of myofibers; they persist in mature skeletal muscles for growth and regeneration post injury. During myotonic dystrophy type 1 (DM1), a complex autosomal-dominant neuromuscular disease, the differentiation of skeletal myoblasts into functional myotubes is impaired, resulting in muscle wasting and weakness. The mechanisms leading to this altered differentiation are not fully understood. Here, we demonstrate that the calcium- and voltage-dependent potassium channel, KCa1.1 (BK, Slo1, KCNMA1), regulates myoblast proliferation, migration, and fusion. We also show a loss of plasma membrane expression of the pore-forming α subunit of KCa1.1 in DM1 myoblasts. Inhibiting the function of KCa1.1 in healthy myoblasts induced an increase in cytosolic calcium levels and altered nuclear factor kappa B (NFκB) levels without affecting cell survival. In these normal cells, KCa1.1 block resulted in enhanced proliferation and decreased matrix metalloproteinase secretion, migration, and myotube fusion, phenotypes all observed in DM1 myoblasts and associated with disease pathogenesis. In contrast, introducing functional KCa1.1 α-subunits into DM1 myoblasts normalized their proliferation and rescued expression of the late myogenic marker Mef2. Our results identify KCa1.1 channels as crucial regulators of skeletal myogenesis and suggest these channels as novel therapeutic targets in DM1.

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Ion channels and anti-cancer immunity

Cited by 50 publications

References 89 publications

KCa1.1 Inhibition Attenuates Fibroblast‐like Synoviocyte Invasiveness and Ameliorates Disease in Rat Models of Rheumatoid Arthritis

KCa1.1 Inhibition Attenuates Fibroblast‐like Synoviocyte Invasiveness and Ameliorates Disease in Rat Models of Rheumatoid Arthritis

Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy

Functional KCa1.1 channels are crucial for regulating the proliferation, migration and differentiation of human primary skeletal myoblasts

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