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Targeted therapy against cancer plays a key role in delivering safer and more efficient treatments. In the last decades, ion channels have been studied for their participation in oncogenic processes because their aberrant expression and/or function have been associated with different types of malignancies, including ovarian, cervical, and endometrial cancer.
- gynecological cancer
- personalized medicine
- ovarian cancer
- endometrial cancer
- cervical cancer
- sodium channels
1. Introduction
Sodium channels can be divided into two types, voltage-gated sodium channels (NaV) and epithelial sodium channels (ENaC). NaV are transmembrane proteins composed by a pore-forming α–subunit of six transmembrane helical segments (S1 to S6) that can be coupled with 1 or 2 β–subunits. In humans, the family is composed by nine different alpha subunits: NaV1.1 (SCN1A), NaV1.2 (SCN2A), NaV1.3 (SCN3A), NaV1.4 (SCN4A), NaV 1.5 (SCN5A), NaV1.6 (SCN8A), NaV1.7 (SCN9A), NaV1.8 (SCN10A), and NaV1.9 (SCN11A) [1]. They are found in several cell types and participate in depolarizing the cell membrane, allowing the entrance of sodium into the cell and generating action potentials in excitable cells; they are also found in non-excitable cells, participating in the regulation of proliferation and migration. Therefore, alterations in their function or expression have been associated with several types of tumors, including gynecological cancers (Table 1) [2].
2. Endometrial Cancer
Sodium channels in endometrial cancer (EC) have been less studied. In EC biopsies, NaV1.7 is overexpressed in 75% of samples analyzed, compared to adjacent non-cancerous tissue. A higher expression was also correlated with tumor size and local lymph node metastasis (LNM) and associated with poor prognosis. The role of Nav1.7 in EC was analyzed by activating the channel with veratridine, resulting in decreased cell apoptosis and increased cell invasion, while blocking the channel with PF-05089771 generated apoptosis and decreased invasion [3]. These results strongly suggest NaV1.7 channels as potential EC biomarkers and targets. The clearly identified tumor-promoting role of these channels can be exploited in personalized medicine.
3. Ovarian Cancer
NaV channels are upregulated in OC cells, predominantly NaV1.1, NaV1.3, NaV1.4, and NaV1.5, compared to normal ovaries. Blocking NaV channels with 30 µM of tetrodotoxin reduces migration and invasion in Caov-3 and SK-OV-3 cell lines. In patient samples with OC with LNM, NaV1.5 mRNA expression level is higher compared to the normal ovary and ovarian cancer without LNM. In accordance, NaV1.5 protein expression was found in OC with LNM but not in the normal ovary [4]. Furthermore, blocking NaV1.5 channels with eicosapentaenoic acid (EPA) diminishes cell migration and proliferation in the SK-OV-3 cell line in a dose-dependent manner by increasing the inactivation of the channel [5]. In cancer cells, NaV α and β subunits regulate migration, invasion, and metastasis. Data analysis of SCNN1A (sodium channel epithelial 1 subunit alpha) levels in OC patients shows a higher channel expression compared to normal ovary samples, and this correlates with a poorer overall survival. Channel overexpression was also observed in SK-OV-3, HO-8910, OVCAR-3, and CoC1 cell lines by RT-qPCR using the normal ovary cell line IOSE80 as a control. Accordingly, knockout of the SCNN1A reduced cell migration and invasion in SK-OV-3 cells; these effects were explained in part by their participation in the epithelial-to-mesenchymal transition (EMT), since SCNN1A silencing promotes the expression of E-cadherin, and reduces the expression of vimentin, N-cadherin, and Snail proteins [6]. This is consistent with Nav α subunits, where they also participate by promoting metastasis characteristic in breast and prostate cancer [7]. In the case of NaV β subunits, RNA sequencing analysis revealed Nav channel expression in 48 ovarian cancer cell lines, showing a reduced expression of SCN8A (NaV1.6) and SCN1B (sodium voltage-gated channel beta subunit 1) in cancer cells. Furthermore, microarray analysis of OC tumors from patients showed a higher overall survival (OS) in patients that express lower levels of SCN8A, and poorer OS with lower levels of SCN1B [8]. SCN1B has been linked to tumor growth, metastasis, and vascularization in a xenograft model of breast cancer [9]. These observations suggest that the analysis of Nav channel expression may lead to improved clinical management of OC patients. In addition, these observations suggest that the association of sodium channels with cancer involves different molecular mechanisms, depending on the type of sodium channel and may include non-conducting functions via NaV β subunit-mediated adhesion. This differential participation supports the precise characterization of the sodium channel expression pattern in OC patients to improve personalized medicine.
4. Cervical Cancer
In HPV16- positive cervical cancer (CCa) biopsies and in cervical cancer primary cell cultures, NaV1.6 and Nav1.7b mRNA overexpression was found when compared to non-cancerous biopsies; although protein expression was found in CCa and non-cancerous samples by immunohistochemistry, the pattern of positive cells was more widely distributed in all the sections of squamous epithelial tissue in CCa biopsies [10]. NaV1.6 expression was related to increased invasive capacity in CCa cells, and protein expression was more abundant in CCa than in noncancerous biopsies [11]. On the contrary, overexpression of ENaC in CCa can be a better prognosis marker. RNA sequencing data from human CCa, showed a better outcome when SCNN1A, SCNN1B, and SCNN1G are simultaneously overexpressed; interestingly, a higher expression was observed in normal tissues and in low-grade CCa patients [12]. Therefore, ENaC channels comprise potential biomarkers for a better prognosis in CCa patients [12]. Because CCa is associated not only with HPV infection, but with other factors, including hormone use and smoking, it would be very interesting to perform preclinical studies concerning the regulation of sodium channels by CCa risk factors. In addition, epidemiological studies analyzing sodium channel expression in smokers or hormone using CCa patients is deserved.
In addition, the regulation of sodium channel expression in normal excitable cells should be studied. How are these channels regulated in such a manner that cell proliferation is controlled? Because sodium fluxes change the membrane potential, studying the regulation of membrane potential by cancer-associated factors (and vice-versa) will provide relevant insights into cancer development.
Table 1. Preclinical and clinical findings correlating sodium channels with gynecological cancers.
| Channel | In Vitro | Animal Models | Clinical Observations | Reference |
|---|---|---|---|---|
| Endometrial Cancer | ||||
| NaV1.7 | Blockade decreases invasion and promotes apoptosis, where activation increases invasion in primary cultures. | mRNA overexpression associated with tumor size, metastasis, and poor prognosis. | [3] | |
| Cervical cancer | ||||
| NaV1.2 | High mRNA expression in primary cultures transfected with the E7 oncogene. | High mRNA expression in cancerous biopsies compared to normal biopsies. | [13] | |
| NaV1.6 | mRNA overexpression in primary cultures increases invasive cell capacity, mediated by MMP2 activity. | More extensive protein pattern expression in tissue biopsies of cervical cancer compared to non-cancerous biopsies. | [10][11] | |
| NaV1.7 | mRNA overexpression in primary cultures. | More extensive protein pattern expression in tissue biopsies of cervical cancer compared to non-cancerous biopsies. | [10] | |
| Ovarian cancer | ||||
| NaV1.5 | Blockade with TTX decreases cell migration and invasion in Caov-3 and SK-OV-3 cells. EPA inactivates the channel and reduced migration and proliferation in SK-OV-3 cells. |
Express in ovarian cancer with lymph node metastasis but not in normal ovary. | [4][14] | |
| NaV1.6 | RNAseq data analysis shows lower expression in 48 ovarian cell lines. | Higher overall survival in patients with lower expression. | [8] | |
| SCNN1A | Overexpressed in SK-OV-3, HO-8910, OVCAR-3, and CoC1 cell lines. | Overexpressed in sample patients obtained by database analysis. | [6] | |
This entry is adapted from the peer-reviewed paper 10.3390/ph16060800
References
- de Lera Ruiz, M.; Kraus, R.L. Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications. J. Med. Chem. 2015, 58, 7093–7118.
- Black, J.A.; Waxman, S.G. Noncanonical roles of voltage-gated sodium channels. Neuron 2013, 80, 280–291.
- Liu, J.; Tan, H.; Yang, W.; Yao, S.; Hong, L. The voltage-gated sodium channel Na(v)1.7 associated with endometrial cancer. J. Cancer 2019, 10, 4954–4960.
- Gao, R.; Shen, Y.; Cai, J.; Lei, M.; Wang, Z. Expression of voltage-gated sodium channel alpha subunit in human ovarian cancer. Oncol. Rep. 2010, 23, 1293–1299.
- Liu, J.; Liu, D.; Liu, J.J.; Zhao, C.; Yao, S.; Hong, L. Blocking the Nav1.5 channel using eicosapentaenoic acid reduces migration and proliferation of ovarian cancer cells. Int. J. Oncol. 2020, 57, 1234.
- Wu, L.; Ling, Z.H.; Wang, H.; Wang, X.Y.; Gui, J. Upregulation of SCNN1A Promotes Cell Proliferation, Migration, and Predicts Poor Prognosis in Ovarian Cancer Through Regulating Epithelial-Mesenchymal Transformation. Cancer Biother. Radiopharm. 2019, 34, 642–649.
- Patel, F.; Brackenbury, W.J. Dual roles of voltage-gated sodium channels in development and cancer. Int. J. Dev. Biol. 2015, 59, 357–366.
- Brummelhuis, I.S.; Fiascone, S.J.; Hasselblatt, K.T.; Frendl, G.; Elias, K.M. Voltage-Gated Sodium Channels as Potential Biomarkers and Therapeutic Targets for Epithelial Ovarian Cancer. Cancers 2021, 13, 5437.
- Nelson, M.; Millican-Slater, R.; Forrest, L.C.; Brackenbury, W.J. The sodium channel beta1 subunit mediates outgrowth of neurite-like processes on breast cancer cells and promotes tumour growth and metastasis. Int. J. Cancer 2014, 135, 2338–2351.
- Hernandez-Plata, E.; Ortiz, C.S.; Marquina-Castillo, B.; Medina-Martinez, I.; Alfaro, A.; Berumen, J.; Rivera, M.; Gomora, J.C. Overexpression of NaV 1.6 channels is associated with the invasion capacity of human cervical cancer. Int. J. Cancer 2012, 130, 2013–2023.
- Lopez-Charcas, O.; Espinosa, A.M.; Alfaro, A.; Herrera-Carrillo, Z.; Ramirez-Cordero, B.E.; Cortes-Reynosa, P.; Perez Salazar, E.; Berumen, J.; Gomora, J.C. The invasiveness of human cervical cancer associated to the function of Na(V)1.6 channels is mediated by MMP-2 activity. Sci. Rep. 2018, 8, 12995.
- Song, C.; Lee, Y.; Kim, S. Bioinformatic Analysis for the Prognostic Implication of Genes Encoding Epithelial Sodium Channel in Cervical Cancer. Int. J. Gen. Med. 2022, 15, 1777–1787.
- Diaz, D.; Delgadillo, D.M.; Hernández-Gallegos, E.; Ramírez-Domínguez, M.E.; Hinojosa, L.M.; Ortiz, C.S.; Berumen, J.; Camacho, J.; Gomora, J.C. Functional expression of voltage-gated sodium channels in primary cultures of human cervical cancer. J. Cell Physiol. 2007, 210, 469–478.
- Liu, J.; Liu, D.; Liu, J.J.; Zhao, C.; Yao, S.; Hong, L. Blocking the Nav1.5 channel using eicosapentaenoic acid reduces migration and proliferation of ovarian cancer cells. Int. J. Oncol. 2018, 53, 855–865.
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