Chloride channel-3 promotes tumor metastasis by regulating membrane ruffling and is associated with poor survival

Abstract

The chloride channel-3 (ClC-3) protein is known to be a component of Cl− channels involved in cell volume regulation or acidification of intracellular vesicles. Here, we report that ClC-3 was highly expressed in the cytoplasm of metastatic carcinomatous cells and accelerated cell migration in vitro and tumor metastasis in vivo. High-grade expression of cytoplasmic ClC-3 predicted poor survival in cancer patients. We found that independent of its volume-activated Cl− channel properties, ClC-3 was able to promote cell membrane ruffling, required for tumor metastasis. ClC-3 mediated membrane ruffling by regulating keratin 18 phosphorylation to control β1 Integrin recycling. Therefore, cytoplasmic ClC-3 plays an active and key role in tumor metastasis and may be a valuable prognostic biomarker and a therapeutic target to prevent tumor spread.

The AQP-3 water channel is a pivotal modulator of glycerol-induced chloride channel activation in nasopharyngeal carcinoma cells

“…ClC-3, a member of the voltage-gated chloride channel family, shows the properties of cell cycle-dependent expression and subcellular distribution, and plays an important role in the regulation of cell proliferation, migration and apoptosis, especially in cancerous cells (Hong et al, 2015;Liu et al, 2013;Mao et al, 2012Mao et al, , 2013Xu et al, 2014;Zhang et al, 2013a). The inducible ClC-3 gene deletion eliminating native VRAC in adult mice overwhelmingly suggested that ClC-3 is a key component of native VRAC in mammalian heart, not in the brain (Xiong et al, 2010).…”

Activation of ClC‐3 chloride channel by 17β‐estradiol relies on the estrogen receptor α expression in breast cancer

“…Our and other labs have demonstrated that ClC‐3 is a candidate of the channel protein mediating volume‐activated Cl − currents (Xu et al, ; Zhu et al, ). The above results indicated that the properties of 17β‐E2‐activated Cl − currents were similar to the volume‐activated Cl − currents.…”

Transcriptional repression of human epidermal growth factor receptor 2 by ClC‐3 Cl−/H+ transporter inhibition in human breast cancer cells

“…In MDA‐MB‐453 cells, siRNA‐mediated inhibition of ClC‐3 Cl − /H + transporter exerted transcriptional repression of HER2 (Figure ). ANO1 and ClC‐3 both promote tumor metastasis and are associated with a poor prognosis . ANO1 proteins are localized at the plasma membrane and regulate membrane potential, whereas ClC‐3 proteins are distributed among intracellular organelles such as endosomes and lysosomes, and are involved in vesicular acidification and Cl − accumulation as a Cl − /H + transporter .…”

“…ANO1 and ClC-3 both promote tumor metastasis and are associated with a poor prognosis. 6,29 ANO1 proteins are localized at the plasma membrane and regulate membrane potential, 30 whereas ClC-3 proteins are distributed among intracellular organelles such as endosomes and lysosomes, and are involved in vesicular acidification and Cl − accumulation as a Cl − /H + transporter. 2,31 As shown in Figure 3 6B); however, the siRNA-mediated inhibition of CLIC1 did not repress HER2 transcription in either cell (Figures 2A and 6C).…”