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.

Cellular sheddases are induced by Merkel cell polyomavirus small tumour antigen to mediate cell dissociation and invasiveness

“…MCPyV ST has emerged as the major transforming factor in MCPyV-positive MCC. Recently we reported a potential role for MCPyV ST in MCC metastasis, whereby ST cultivates a pro-migratory cell phenotype by destabilising microtubules [ 30 ], inducing filopodia formation [ 31 ] and modulating cellular chloride channels [ 32 ]. Cancer metastasis occurs via a series of complex events that are collectively known as the invasion-metastasis cascade [ 61 ].…”

“…These metastatic hallmarks include loss of cell adhesion, gain of cell motility, dissemination via the vasculature, and colonisation of distant sites [ 28 , 29 ]. Recent quantitative proteomic studies suggest MCPyV ST expression can promote cell motility and migration [ 30 – 32 ] by inducing differential expression of cellular proteins involved in microtubule [ 30 ] and actin-associated cytoskeletal organization and dynamics [ 31 ], leading to microtubule destabilization and filopodium formation. These results suggest that MCPyV may be associated with the highly metastatic nature of MCC, and is supported by studies showing that engraftment of MCC cell lines into SCID mice results in circulating tumour cells and metastasis formation [ 33 ].…”

Intracellular Chloride Channels: Novel Biomarkers in Diseases

“…Modulation of CLIC1 expression by micro RNA, hsa-mir-372 predicts the poor prognosis of patients affected with gall bladder cancers (Zhou et al, 2017) and is important for the migration and invasion of gall bladder cancer cells (He et al, 2018). CLIC1, along with CLIC4, contributes to the virus-mediated motility of Merkel cell carcinoma (Stakaityte et al, 2018).…”

Merkel Cell Polyomavirus Small Tumor Antigen Activates Matrix Metallopeptidase-9 Gene Expression for Cell Migration and Invasion

“…2A). (16–18, 40, 41). Interestingly, sT mutant, sT LSDm , showed a decrease in sT-induced cell migration.…”