The cellular chloride channels CLIC1 and CLIC4 contribute to virus-mediated cell motility.

Abstract

Ion channels regulate many aspects of cell physiology, including cell proliferation, motility, and migration, and aberrant expression and activity of ion channels is associated with various stages of tumor development, with K+ and Cl- channels now being considered the most active during tumorigenesis. Accordingly, emerging in vitro and preclinical studies have revealed that pharmacological manipulation of ion channel activity offers protection against several cancers. Merkel cell polyomavirus (MCPyV) is a major cause of Merkel cell carcinoma (MCC), primarily because of the expression of two early regulatory proteins termed small and large tumor antigens (ST and LT, respectively). Several molecular mechanisms have been attributed to MCPyV-mediated cancer formation but, thus far, no studies have investigated any potential link to cellular ion channels. Here we demonstrate that Cl- channel modulation can reduce MCPyV ST-induced cell motility and invasiveness. Proteomic analysis revealed that MCPyV ST up-regulates two Cl- channels, CLIC1 and CLIC4, which when silenced, inhibit MCPyV ST-induced motility and invasiveness, implicating their function as critical to MCPyV-induced metastatic processes. Consistent with these data, we confirmed that CLIC1 and CLIC4 are up-regulated in primary MCPyV-positive MCC patient samples. We therefore, for the first time, implicate cellular ion channels as a key host cell factor contributing to virus-mediated cellular transformation. Given the intense interest in ion channel modulating drugs for human disease. This highlights CLIC1 and CLIC4 activity as potential targets for MCPyV-induced MCC.

• Authors: Gabrielė Stakaitytė, Nnenna Nwogu, Jonathan D Lippiat, G Eric Blair, Krzysztof Poterlowicz, James R Boyne, Andrew Macdonald, Jamel Mankouri, Adrian Whitehouse
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 12 Pg. 4582-4590 (03 23 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 29462791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antigens, Viral, Tumor
• CLIC1 protein, human
• CLIC4 protein, human
• Chloride Channels
• Chlorides
• Proteome

Topics

• Antigens, Viral, Tumor (genetics, metabolism)
• Carcinoma, Merkel Cell (epidemiology, pathology, virology)
• Cell Movement
• Cell Proliferation
• Chloride Channels (genetics, metabolism)
• Chlorides (metabolism)
• HEK293 Cells
• Humans
• Incidence
• Merkel cell polyomavirus (physiology)
• Neoplasm Invasiveness
• Polyomavirus Infections (complications, pathology, virology)
• Proteome (analysis)
• Skin Neoplasms (epidemiology, secondary, virology)
• Tumor Virus Infections (complications, pathology, virology)