Role of ion channels in gastrointestinal cancer

Abstract

In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca2+), sodium (Na+), potassium (K+), chloride (Cl-) and zinc (Zn2+) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K+ channel and CFTR Cl- channel in colorectal cancer (CRC). Ca2+ is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn2+ transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K+ channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K+ channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl- channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity c...

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“…However, the detailed regulation mechanisms are still poorly understood. Intracellular Ca 2+ plays important roles in the regulation of a variety of cellular processes, such as cell cycle, apoptosis, and migration [21] [22]. Recent studies have shown that inositol trisphosphate receptor type 1 (IP 3 R 1 )-mediated Ca 2+ release increases the cytosolic free Ca 2+ level, which induces miscarriage in rat [23].…”

The role of TRPV1 ion channels in the suppression of gastric cancer development

“…Although the occurrence and progression of cancer are complex, numerous findings indicate that aberrant intracellular Ca 2+ ([Ca 2+ ] i ) signaling is involved in the development of several types of gastrointestinal (GI) cancers, including GC and colon cancer [4]. Since plasma membrane Ca 2+ -permeable channels play important roles in the regulation of [Ca 2+ ] i , their aberrant expression and function are positively associated with the occurrence and development of GI tumors [5,6]. Consistently, we revealed that activation of G protein-coupled receptors (GPCRs), such as Ca 2+ sensing receptors (CaSR) and vasoactive intestinal polypeptide (VIP) receptors, promotes GC progression via transient receptor potential vanilloid receptor 4 (TRPV4) channels and the Ca 2+ signaling [7,8].…”

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

“…These include multiple signal transduction and downstream signaling events, including regulation of gene expression, secretion of enzymes and hormones, and intracellular communication between compartments (Chen et al, 1994;Tolon et al, 1996;Stock and Schwab, 2015). A stable regulation of these processes maintains normal tissue homeostasis, such as cell cycle progression, migration, and apoptosis (Kunzelmann, 2005;Kunzelmann, 2016;Prevarskaya et al, 2018;Anderson et al, 2019). Accordingly, dysregulated expression as well as altered function of ion channels are related to a great number of diseases (Kim, 2014), and can drive the transformation from normal to malignant cell behavior (Litan and Langhans, 2015).…”