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Intracellular chloride channels: critical mediators of cell viability and potential targets for cancer therapy
1Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Abstract:
The passage of ions to form and maintain electrochemical gradients is a key element for regulating cellular activities and is dependent on specific channel proteins or complexes. Certain ion channels have been the targets of pharmaceuticals that have had impact on a variety of cardiovascular and neurological diseases. Chloride channels regulate the movement of a major cellular anion, and in so doing they in part determine cell membrane potential, modify transepithelial transport, and maintain intracellular pH and cell volume. There are multiple families of chloride channel proteins, and respiratory, neuromuscular, and renal dysfunction may result from mutations in specific family members. Interest in chloride channels related to cancer first arose when the multidrug resistance protein (MDR/P-glycoprotein) was linked to volume-activated chloride channel activity in cancer cells from patients undergoing chemotherapy. More recently, CLC, CLIC, and CLCA intracellular chloride channels have been recognized for their contributions in modifying cell cycle, apoptosis, cell adhesion, and cell motility. Moreover, advances in structural biology and high-throughput screening provide a platform to identify chemical compounds that modulate the activities of intracellular chloride channels thereby influencing chloride ion transport and altering cell behavior. This review will focus on several chloride channel families that may contribute to the cancer phenotype and suggest how they may serve as novel targets for primary cancer therapy.
Insights
Chloride channels are crucial for cell function and are increasingly implicated in cancer. Targeting these channels offers a promising new avenue for primary cancer therapy.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Ion channels, particularly chloride channels, regulate essential cellular processes like membrane potential, pH, and cell volume.
- Dysfunction in chloride channels is linked to various diseases, including respiratory, neuromuscular, and renal disorders.
- Early research connected multidrug resistance protein (MDR/P-glycoprotein) to chloride channel activity in chemotherapy-resistant cancer cells.
Purpose of the Study:
- To review the role of various chloride channel families in the development of the cancer phenotype.
- To explore the potential of intracellular chloride channels as novel targets for primary cancer therapy.
Main Methods:
- Literature review focusing on chloride channel families and their involvement in cancer.
- Discussion of advances in structural biology and high-throughput screening for identifying modulators.
- Analysis of how chloride channel activity influences cancer cell behavior.
Main Results:
- Several chloride channel families (CLC, CLIC, CLCA) are recognized for their roles in cell cycle, apoptosis, adhesion, and motility.
- Modulating intracellular chloride channel activity can alter cancer cell behavior.
- Structural biology and screening technologies facilitate the discovery of chloride channel modulators.
Conclusions:
- Chloride channels play a significant role in various aspects of cancer biology.
- Targeting specific chloride channel families presents a novel strategy for primary cancer treatment.
- Further research into chloride channel modulators could lead to new therapeutic interventions.
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