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

Figure 1

Two models for the effect of CFTR deficiency on Wnt/β-catenin signaling. A: CFTR deficiency promotes Wnt/β-catenin signaling. CFTR deficiency causes increased intracellular pH. Increased pH promotes association with Dishevelled (DVL) at the membrane and with the Wnt receptor Frizzled (FZD). DVL association with FZD enhances Wnt/β-catenin signaling leading to increased nuclear localization of β-catenin. Nuclear β-catenin promotes transcription of genes involved in proliferation, survival and stemness[93]; B: CFTR deficiency inhibits Wnt/β-catenin signaling. CFTR deficiency releases membrane associated β-catenin to the cytosol where it is degraded thus decreasing Wnt/β-catenin activity. Loss of β-catenin releases NF-κB which translocates to the nucleus where it promotes transcription of inflammatory targets[145]. FZD: Frizzled; DVL: Dishevelled; AJ: Adherens junctions.

Figure 2

CFTR deficiency disrupts epithelial barrier integrity. CFTR deficiency disrupts the mucin barrier and adherens junctions. This allows bacterial contact with the apical and basal surfaces of the epithelial layer. Contact with the apical layer stimulates inflammatory signaling via toll-like receptors. Contact with the basal layer leads to immune cell infiltration which results in additional inflammatory signaling. AJ: Adherens junctions; TLR: Toll-like receptors.

Figure 3

Oncogenic mechanisms of selected ion channels. Because ion channels influence the basic biochemical environment of the cell as well as complex interactions with other proteins, they have profound and pleiotropic effects on cell function. As a result, it is often difficult to determine specific mechanisms for oncogenic phenotypes. However, progress has been made in defining mechanisms in some cases. This figure shows examples from each category of channels with accompanying pathways linking dysregulation of channel function to tumorigenesis. For additional information and references please see text and Tables 1-5. GI: Gastrointestinal; EMT: Epithelial to mesenchymal transition; TRP: Transient receptor potential; SOCE: Store-operated calcium entry; VGSC: Voltage-gated sodium channels; STIM1: Stromal interaction protein 1.