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 Na_V1.5 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 Na_V1.5 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 can contribute to malignant transformation and tumor progression. Further, because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation, they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs.

Keywords: Ion channels, Gastrointestinal cancer, Colorectal cancer, Gastric cancer, Pancreatic cancer, Esophageal cancer, Hepatocellular carcinoma, Prognostic biomarker, Novel therapies, Clinical targets

Core tip: Ion channels play an essential function in the physiology of the GI tract. There is increasing evidence that they are dysregulated at all stages of gastrointestinal (GI) cancer, from early initiation to metastasis. This information provides for the use of ion channel expression as useful clinical prognostic biomarkers in GI cancer. Perhaps more importantly new therapeutic modalities targeting ion channels in the GI tract, including the potential to target their dysregulation in GI cancers are becoming increasingly feasible. This strategy includes the repurposing of existing drugs that are used to treat other ion channel pathologies, or other diseases altogether. This review seeks to provide an overview of the role of ion channels in GI cancers with an emphasis on the potential for new therapies that target them.