Ion channels are integral membrane proteins that allow the passage of ions through the plasma membrane and participate in diverse biological functions, from regulating the membrane potential to promoting signal transduction, contraction, and secretion, among many others. The potassium channel family is the most widely distributed group of ion channels, composed of dimers or tetrameric integral membrane proteins that regulate the flux of potassium ions. They are divided into four families based on the classification of the International Union of Basic and Clinical Pharmacology (IUPHAR): (i) voltage-gated K+ channels (Kv) encoded by forty genes in twelve subfamilies, (ii) inwardly rectifying K+ channels, (Kir) encoded by fifteen genes classified in seven subfamilies, (iii) calcium- and sodium-activated potassium channels (KCa, KNa) encoded by eight genes in five subfamilies, and (iv) two-pore domain K+ channels (K2P) encoded by fifteen genes in six subfamilies. Potassium channels are aberrantly expressed in different cancer cell lines and cancer tissues, and there is mounting evidence that supports the association of potassium channels with the hallmarks of cancer, including cell proliferation, invasion, and migration; in accordance, blocking or suppressing their expression or activity has antineoplastic features in different types of tumors in both, in vitro and in vivo studies, strongly suggesting them as candidates for targeted therapy.
Channel | In Vitro | Animal Models | Clinical Observations | Reference |
---|---|---|---|---|
Endometrial Cancer | ||||
KV11.1 | High expression of KCNE and HERG genes in the AN3-CA, KLE, and Ishikawa cell lines. | Higher frequency of RNA and protein expression in primary human tumors compared to non-cancerous tissues. | [24,25][17][18] | |
KCa1.1 | Silencing with siRNA reduced cell proliferation, cell migration, and p-MEK1/2 and p-ERK1/2 expression in Ishikawa cells. Overexpression promotes cell proliferation and migration, and blockage with IBTX reduces cell proliferation in HEC-1-B cells. |
Silencing in xenografts transplanted in nude mice produced smaller tumors compared to control mice. | Higher protein staining in type I endometrial adenocarcinoma tissue compared to normal and atypical endometrial tissues. | [14,15][7][8] |
KCa3.1 | Downregulation by siRNA in HEC-1-A and KLE cells inhibits proliferation. Silencing by shRNA or blockage with TRAM-34 reduces cell cycle progression, and TRAM-34 diminishes migration and MMP2 expression in HEC-1-A and Ishikawa cells. |
TRAM-34 and clotrimazole reduced tumor formation of HEC-1-A cells in nude mice. | Higher expression of mRNA and protein levels in endometrial cancer tissues compared to normal tissues. | [9,10][2][3] |
Cervical cancer | ||||
KV1.1 | Knockdown suppresses cell proliferation, migration, invasion, and protein levels of Hhg and Wnt1 in HeLa cells. | Knockdown in HeLa cells generated smaller xenograft tumors and prolonged survival in nude mice. | Higher protein expression in CCa tissues correlates with poor prognosis. | [22][15] |
KV3.4 | Inactivation of the AKT pathway and inhibition of cell migration by blockage with BDS-II in Hela cells. | [21][14] | ||
KV10.1 | Higher expression in HeLa, SiHa, and primary cultures of cervical cancer. Imipramine and astemizole decrease channel expression and increase apoptosis in E6/E7-transfected keratinocytes. Decreased proliferation and increased apoptosis of HeLa, SiHa, CaSki, INBL, and C-33A cells with astemizole treatment. Decreased mRNA and proliferation with calcitriol treatment in the SiHa cell line. |
Inhibition of tumor growth in xenograft mice with tetrandrine treatment. Increased mRNA and protein expression in CCa tissues of transgenic mice K14E7 treated with estrogens. |
Higher expression in high-grade cervical lesions compared to low-grade lesions and normal tissues. | [26,27,28,29,30][19][20][21][22][23] |
Kir6.2 | Overexpression of mRNA in HeLa cells, and blockage with glibenclamide reduces cell viability. | Higher expression in invasive tumors compared to low or non-invasive tumors. | [31][24] | |
KCa1.1 | Estradiol treatment increased protein and mRNA expression in K14E7 transgenic mice with CCa. | Higher intensity of immunostaining in biopsies of carcinoma in situ. | [12][5] | |
KCa3.1 | Downregulation by siRNA increased apoptosis in HeLa cells. Increased uptake of dye H33258 dependent on KCa3.1 is observed in cervical carcinoma cell lines (CXT) compared to nonmalignant cervical epithelial cell strains (HCX). Clotrimazole reduces mRNA expression and changes HeLa cell morphology. |
mRNA and protein overexpression in cervical cancer tissues. | [16][25][26] | |
Ovarian cancer | ||||
K2p2.1 K2p10.1 |
Curcumin increases late apoptosis and decrease proliferation in SK-OV-3 and OVCAR-3 cells. | Expression is increased in cancer samples compared to normal ovarian samples. | [34][27] | |
K2p9.1 | Reduction in proliferation and increase in late apoptosis in SK-OV-3 and OVCAR-3 cells with methanandamide treatment. | Significant correlation of immunostaining with tumor stage in patient biopsies. | [35][28] | |
KV10.1 KV11.1 | 4-aminopyridine and tetraethylammonium inhibited proliferation in SK-OV-3 cells. Imipramine increases apoptosis levels and decreases proliferation in SK-OV-3 cells. Ergtoxin inhibits the proliferation of SK-OV-3 cells. |
Higher expression in OC tissues compared to noncancerous tissue. | [36,37][29][30] | |
KV10.1 | siRNA targeting sensitizes SK-OV-3 and TYK cells to cisplatin-induced apoptosis. | High expression compared to normal tissues. | [38][31] | |
KV11.1 | Berberine reduces mRNA and protein levels in SK-OV-3 cells. | Berberine decreases tumor growth in xenografts compared to the control group. | High protein expression in tumor tissues compared to non-tumor tissues. | [17][10] |
KCa1.1 | Correlation of miR-31 levels and resistance to cisplatin in A2780 cells. | Loss of expression is associated with cisplatin resistance. | [39][32] | |
KCa2.3 | Low mRNA and protein expression in samples of ovarian serous cystadenocarcinomas compared to normal ovarian tissues and correlated with shorter disease-free and overal survival. | [19][12] |