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Ramírez, A.; Ogonaga-Borja, I.; Acosta, B.; Chiliquinga, A.J.; De La Garza, J.; Gariglio, P.; Ocádiz-Delgado, R.; Bañuelos, C.; Camacho, J. Association between K+ Channels and Gynecological Cancers. Encyclopedia. Available online: https://encyclopedia.pub/entry/45366 (accessed on 20 June 2024).
Ramírez A, Ogonaga-Borja I, Acosta B, Chiliquinga AJ, De La Garza J, Gariglio P, et al. Association between K+ Channels and Gynecological Cancers. Encyclopedia. Available at: https://encyclopedia.pub/entry/45366. Accessed June 20, 2024.
Ramírez, Ana, Ingrid Ogonaga-Borja, Brenda Acosta, Andrea Jazmín Chiliquinga, Jaime De La Garza, Patricio Gariglio, Rodolfo Ocádiz-Delgado, Cecilia Bañuelos, Javier Camacho. "Association between K+ Channels and Gynecological Cancers" Encyclopedia, https://encyclopedia.pub/entry/45366 (accessed June 20, 2024).
Ramírez, A., Ogonaga-Borja, I., Acosta, B., Chiliquinga, A.J., De La Garza, J., Gariglio, P., Ocádiz-Delgado, R., Bañuelos, C., & Camacho, J. (2023, June 08). Association between K+ Channels and Gynecological Cancers. In Encyclopedia. https://encyclopedia.pub/entry/45366
Ramírez, Ana, et al. "Association between K+ Channels and Gynecological Cancers." Encyclopedia. Web. 08 June, 2023.
Association between K+ Channels and Gynecological Cancers
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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.

gynecological cancer personalized medicine ion channels ovarian cancer endometrial cancer cervical cancer

1. Endometrial Cancer

In endometrial cancer (EC), overexpression of potassium channels has been reported in several cell lines and tumor tissues [1]. The intermediated-conductance Ca2+-activated K+ channel 3.1. (KCa3.1, KCNN4) mRNA expression and the corresponding protein level (detected by Western blot) are increased in EC tissues, compared to normal tissue and atypical hyperplasia. Inhibition of KCNN4 activity by blocking the channel with clotrimazole or TRAM-34, or knockout with siRNA, reduces HEC1-A and KLE cell proliferation by arresting the cells in the G0/G1 phase [2], and this was associated with reduced expression of cyclin D1 and cyclin E1 in HEC1-A and Ishikawa cells [3]. On the contrary, activation of KCNN4 induces cell cycle progression to G1 phase [2]. Furthermore, treatment of HEC1-A and Ishikawa cells with TRAM-34 reduces migration with a reduction in MMP-2 expression [3]. In nude mice with tumors of HEC1-A cells that are treated with TRAM-34 or clotrimazole, results showed smaller tumor development versus control groups [2]. Other potassium channel blockers, such as glibenclamide (GLI), 4-aminopyridine (4-AP), and tetraethylammonium (TEA), suppress cell proliferation, besides GLI and 4-AP also reduce migration in the HEC1-A cell line [4].
Another K+ channel, the large-conductance voltage and Ca2+-activated K+ channel (KCa1.1, KCNMA1), is involved in cancer cell proliferation and migration, and it is aberrantly expressed in many types of tumors, including cervical [5], ovarian [6], and endometrial cancers [7][8]. It is involved in cancer cell proliferation and migration. Overexpression of KCNMA1 in HEC-1-B cells by transient transfection increases viability, promotes the cell cycle to S and G2/M phases, and favors migration. Furthermore, the contrary effect is obtained with the inhibitor IBTX or knockdown of KCNMA1. These treatments reduce proliferation and migration, and in vivo studies show a diminished tumor growth rate in nude mice with HEC-1-B xenografts [8]. In 185 tissue samples of type I endometrial cancer, protein expression of KCNMA1 by immunohistochemistry was compared with 40 normal endometrium tissues and 38 atypical endometrial hyperplasia tissues; a significantly higher expression was found in all layers of type I endometrial cancer, and there was more correlation with higher FIGO (International Federation of Gynecology and Obstetrics) stages and lymph node metastasis samples, suggesting the association of these channels with poor prognosis [7]. Thus, despite the need of supplementary research to validate prognosis features and experimental research to underline the mechanism by which KCNMA1 is involved in EC, it may be a future candidate for personalized medicine schemes in patients displaying aberrant expression of the channel.
Potassium channels may have a tumor promoting role in EC, as it occurs in other malignancies. Thus, the fine regulation of these channels by EC-associated factors, including hormones, also deserves further investigation.

2. Ovarian Cancer

Potassium channels have been associated with ovarian cancer (OC) progression and prognosis. One of the most studied K+ channels in cancer, the ether-à-go-go-related potassium channel 1 (KV11.1, KCNH2), is widely overexpressed in many types of cancer and promotes proliferation, migration, and invasion [9]. In ovarian cancer (OC) tumor tissues, higher KCNH2 mRNA and protein expression were found when compared with adjacent non-tumor tissues, and the higher expression of KCNH2 has been associated with lymph node metastasis (LNM) and distant metastasis [10]. One study of the DNA methylation profile of clear cell OC tumors found hypermethylation and reduced mRNA expression of KCNH2; the low levels of KCNH2 in clear cell OC was associated with good prognosis, emphasizing the tumor-promoting role of these channels [11]. To the contrary, microarray analysis of the potassium calcium-activated channel subfamily N member 3 (KCa2.3, KCNN3) revealed a significantly lower expression in OC tissues and in drug-resistant OC, compared with normal tissue and sensitive tissues, respectively. Furthermore, lower staining of KCNN3 by immunohistochemistry was observed in 33 of 57 tissues of OC, compared to a higher expression observed in 6 controls, and a 75% lower expression in drug-resistant tissues compared to 37% in drug-sensitive tissues was observed. These latter findings were correlated with shorter disease-free survival in samples with lower KCNN3 expression, suggesting that KCNN3 could be a tumor suppressor, therapeutic target, and a marker of poor prognosis in OC [12].
The pattern expression of potassium channels in OC may reveal the potential role of these channels as tumor promoters or suppressors. The specific therapeutic approach inhibiting or inducing the expression of certain potassium channels may give advantages for each patient in personalized medicine.

3. Cervical Cancer

Several potassium ion channels have been implicated in the progression of cervical cancer (CCa). For example, KV10.1 (KCNH1) is associated with proliferation, malignant transformation, and tumor growth, and various studies have been conducted to study inhibitors of KCNH1, such as tetrandrine (30 mg/kg/day), that reduce CCa tumor growth in vivo [13]. Likewise, blockage of the KV3.4 (KCNC4) channel with BDS-II inhibits the migration of HeLa cells by 46%, reduces the expression of vimentin, inactivates the AKT pathway by diminishing phospho-AKT (Ser473), and increases activation of PTEN, which is a negative regulator of the AKT pathway and a tumor suppressor [14]. Detecting early stages of cancer development is one of the key factors for a successful treatment. In the case of KCNMA1 (KCa1.1), it has been proposed as an early marker for CCa since higher immunostaining of the protein is more prominent in high-grade dysplasia and cervical cancer tissues [5]. Western blot analysis was used to determine the voltage-gated potassium channel KV1.1 (KCNA1) protein expression, showing its overexpression in CCa cell lines (HeLa, SiHa, and C-33A) compared to normal epithelia tissue, and its knockdown reduces the migration, proliferation, and invasion of HeLa cells associated with decreased Hhg and Wnt protein levels and mitochondrial capacity. Besides, in 20 CCa tissue samples from patients, increased expression of KV1.1 was correlated with poor prognosis and reduced survival time, which suggest KV1.1 as a potential biomarker for tumor development and survival rate in cervical cancer [15]. To improve chemotherapy outcomes, a widely used alternative is to sensitize cancer cells to cytotoxic drugs by increasing their permeability, considering that several anticancer drugs, such as cisplatin and doxorubicin, have low membrane permeability. Bukhari et al. found that the activation of the intermediate conductance Ca2+-activated K+ channels (KCa3.1), which is upregulated in CCa cells, induces H33258 uptake, a cytotoxic DNA-binding cationic dye [16].
The use of specific and general inhibitors of potassium channels is a very promising approach to improve CCa therapy. While some inhibitors may be used as to decrease the malignant properties of cancer cells, the overexpression of some ion channels may also be used to facilitate the entry of anticancer drugs. In this type of cancer, the precise regulation of these channels by human papilloma virus (HPV) oncogenes and hormones is also warranted.
The differential expression of potassium channels in gynecological cancers strongly suggests that different molecular mechanisms are involved in favoring tumor development. Some potassium channels are overexpressed, while others are downregulated, strongly suggesting that potassium currents or membrane potential are not the sole mechanism involved. The potential association of potassium channels with other proteins deserves further investigation.

References

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