Voltage-gated K+ channels promote BT-474 breast cancer cell migration

Abstract

ObjectiveA variety of ion channels have been implicated in breast cancer proliferation and metastasis. Voltage-gated K+ (Kv) channels not only cause repolarization in excitable cells, but are also involved in multiple cellular functions in non-excitable cells. In this study we investigated the role of Kv channels in migration of BT474 breast cancer cells. MethodsTranswell technique was used to separate migratory cells from non-migratory ones and these two groups of cells were subject to electrophysiological examinations and microfluorimetric measurements for cytosolic Ca2+. Cell migration was examined in the absence or presence of Kv channel blockers. ResultsWhen compared with non-migratory cells, migratory cells had much higher Kv current densities, but rather unexpectedly, more depolarized membrane potential and reduced Ca2+ influx. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed the presence of Kv1.1, Kv1.3, Kv1.5, Kv2.1, Kv3.3, Kv3.4 and Kv4.3 channels. Cell migration was markedly inhibited by tetraethylammonium (TEA), a delayed rectifier Kv channel blocker, but not by 4-aminopyridine, an A-type Kv channel blocker. ConclusionsTaken together, our results show that increased Kv channel expression played a role in BT474 cell migration, and Kv channels could be considered as biomarkers or potential therapeutic targets for breast cancer metastasis. The mechanism(s) by which Kv channels enhanced migration appeared unrelated to membrane hyperpolarization and Ca2+ influx.

Toward Hijacking Bioelectricity in Cancer to Develop New Bioelectronic Medicine

“…[123,124] Other specific inhibitors of Kv1.3 include piperine in prostate cancer cells, [125] 5-(4-phenoxybutoxy)psoralen (PAP-1) in leukaemia, [126,127] and rituximab in T-cells. [128] Non-specific Kv blockers such as 4aminopyridine (4-AP) and tetraethylammonium (TEA) have proved effective against glioma [129] and breast cancer [130] cells, respectively. Also, part of the VGPC channels, ether-a-go-go (EAG) potassium selective channels are major regulators of cancer progression, [131] particularly Eag1 (Kv10.1) and hERG1 (Kv11.1).…”

“…[ 123,124 ] Other specific inhibitors of Kv1.3 include piperine in prostate cancer cells, [ 125 ] 5‐(4‐phenoxybutoxy)psoralen (PAP‐1) in leukaemia, [ 126,127 ] and rituximab in T‐cells. [ 128 ] Non‐specific Kv blockers such as 4‐aminopyridine (4‐AP) and tetraethylammonium (TEA) have proved effective against glioma [ 129 ] and breast cancer [ 130 ] cells, respectively.…”

Voltage-Gated Potassium Channels as Regulators of Cell Death

“…However, expression of Kv1.5 shows an inversed correlation with malignancy in some gliomas and non-Hodgkin's lymphomas (Comes et al, 2013(Comes et al, , 2015, while its high expression, along with that of Kv1.3, correlates with leiomyosarcoma proliferation and aggressiveness (Bielanska et al, 2012). In accordance, silencing Kv1.5 expression in osteosarcoma significantly inhibited proliferation and induced a cell cycle arrest at G0/G1 phase (Wu et al, 2015) and channel expression has been linked to proliferation in several works (see e.g., Vallejo-Gracia et al, 2013;Chow et al, 2018).…”

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

“…To date, various kinds of Kv1.5 modulators have been disclosed, herein, we summarize the molecular structures and functionality of different types of Kv1.5 modulators with their chemical structure as follows (Table 1, Figure 2). As shown in Table 1, the existing Kv1.5 modulators can be divided into four categories: clinical cardiovascular drugs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), other clinical drugs (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), drugs in development (29)(30)(31)(32)(33)(34)(35)(36)(37), and natural products (38)(39)(40)(41)(42)(43)(44)(45)(4...…”

“…A variety of natural products have been proven to modulate Kv1.5, but the exploration of novel skeleton could be helpful for the current dilemma. Among the isolated compounds, the main types are terpenoids (38)(39)(40)(41), alakaloids (42)(43)(44)(45)(46)(47), and flavonoids (48)(49)(50). Terpenoids are widely reported to inhibit potassium channels [26][27][28], however, the stability and difficulty in preparation because of the lack of a fluorescence group and the abundance in chiral carbon are worth worrying about in the development.…”