Targeting the Voltage-Dependent K+ Channels Kv1.3 and Kv1.5 as Tumor Biomarkers for Cancer Detection and Prevention

Abstract

Potassium channels (KCh) are a diverse group of membrane proteins that participate in the control of the membrane potential. More than eighty different KCh genes have been identified, which are expressed in virtually all living cells. In addition to nerve and cardiac action potentials, these proteins are involved in a number of physiological processes, including cell volume regulation, apoptosis, immunomodulation and differentiation. Furthermore, many KCh have been reported to play a role in proliferation and cell cycle progression in mammalian cells, and an important number of studies report the involvement of KCh in cancer progression. The voltage dependent potassium (Kv) channels, in turn, form the largest family of human KCh, which comprises about 40 genes. Because Kv1.3 and Kv1.5 channels modulate proliferation of different mammalian cells, these proteins have been analyzed in a number of tumors and cancer cells. In most cancers, the expression patterns of Kv1.3 and Kv1.5 are remodeled, and in some cases, a correlation has been established between protein abundance and grade of tumor malignancy. The list of cancers evaluated is constantly growing, indicating that these proteins may be future targets for treatment. The aim of this review is to provide an updated overview of Kv1.3 and Kv1.5 channels during cancer development. Unlike Kv1.5, Kv1.3 is characterized by a very selective and potent pharmacology, which could lead to specific pharmacological targeting. Because potassium channels may play a pivotal role in tumor cell proliferation, these proteins should be taken into account when designing new cancer treatment strategies.

Voltage-Gated Ptassium Channels Kv1.3 - Potentially New Molecular Target in Cancer Diagnostics and Therapy

“…Moreover, in prostate cancer, the channels' expression is significantly higher in the weakly metastatic LNCaP and AT-2 cell lines than in the strongly metastatic PC3 and Mat-LyLu cell lines [8,25,26]. A significant reduction of the expression of Kv1.3 channels was also observed in the case of pancreas adenocarcinoma, especially in patients with metastasis, where the channels were almost absent [7,8,24]. It has been shown that the reduction of the channels' expression was also probably a consequence of the methylation of the promoter region of the Kv1.3-encoding gene in pancreatic cells.…”

“…Recently, Kv1.3 channels are considered a new, potentially attractive molecular target in both cancer diagnostics and therapy [6][7][8][17][18][19][20]. First of all, several studies have demonstrated altered expression of Kv1.3 in some cancer specimens in comparison with normal tissue [6-8, 17, 18].…”

“…This process was enhanced in patients with metastasis. The survival distribution function showed that patients with a methylated promoter region of the Kv1.3 gene in pancreatic cells have significantly less chance to survive than patients with an unmethylated promoter region of this gene [7,24]. Thus, expression of the Kv1.3 channels can be considered a potential diagnostic marker in some cancer diseases.…”

“…Kv1.3 channels are expressed abundantly in many tissues, both normal and cancer [6][7][8]. Studies performed in the last 10 years provide evidence that Kv1.3 channels are expressed not only in the plasma membrane, but also in the inner mitochondrial membrane [9,10].…”

Increased voltage-dependent K+ channel Kv1.3 and Kv1.5 expression correlates with leiomyosarcoma aggressiveness

“…During the G1/S phase of the cell cycle a temporary hyperpolarization occurs, in which Kv channels are involved (8). The voltage-dependent Kv1.3 and Kv1.5 channels are involved in cell proliferation, and expression remodeling has been described during neoplastic growth (5,9). A number of tissues, such as brain, muscle and the immune system, co-express the two channels (10)(11)(12).…”