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Cancers 2019, 11(1), 102; https://doi.org/10.3390/cancers11010102

Inhibition of Pannexin 1 Reduces the Tumorigenic Properties of Human Melanoma Cells

1
Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6A5C1, Canada
2
Surgery, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6A5C1, Canada
3
Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6A5C1, Canada
4
Oncology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6A5C1, Canada
*
Author to whom correspondence should be addressed.
Received: 18 December 2018 / Revised: 9 January 2019 / Accepted: 10 January 2019 / Published: 16 January 2019
(This article belongs to the Special Issue Ion Channels in Cancer)
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Abstract

Pannexin 1 (PANX1) is a channel-forming glycoprotein expressed in many tissues including the skin. PANX1 channels allow the passage of ions and molecules up to 1 kDa, including ATP and other metabolites. In this study, we show that PANX1 is highly expressed in human melanoma tumors at all stages of disease progression, as well as in patient-derived cells and established melanoma cell lines. Reducing PANX1 protein levels using shRNA or inhibiting channel function with the channel blockers, carbenoxolone (CBX) and probenecid (PBN), significantly decreased cell growth and migration, and increased melanin production in A375-P and A375-MA2 cell lines. Further, treatment of A375-MA2 tumors in chicken embryo xenografts with CBX or PBN significantly reduced melanoma tumor weight and invasiveness. Blocking PANX1 channels with PBN reduced ATP release in A375-P cells, suggesting a potential role for PANX1 in purinergic signaling of melanoma cells. In addition, cell-surface biotinylation assays indicate that there is an intracellular pool of PANX1 in melanoma cells. PANX1 likely modulates signaling through the Wnt/β-catenin pathway, because β-catenin levels were significantly decreased upon PANX1 silencing. Collectively, our findings identify a role for PANX1 in controlling growth and tumorigenic properties of melanoma cells contributing to signaling pathways that modulate melanoma progression. View Full-Text
Keywords: pannexin; PANX1; melanoma; carbenoxolone; probenecid; tumor growth; patient-derived cells; Chick-CAM; xenografts; ATP; Wnt; β-catenin pannexin; PANX1; melanoma; carbenoxolone; probenecid; tumor growth; patient-derived cells; Chick-CAM; xenografts; ATP; Wnt; β-catenin
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Freeman, T.J.; Sayedyahossein, S.; Johnston, D.; Sanchez-Pupo, R.E.; O’Donnell, B.; Huang, K.; Lakhani, Z.; Nouri-Nejad, D.; Barr, K.J.; Harland, L.; Latosinsky, S.; Grant, A.; Dagnino, L.; Penuela, S. Inhibition of Pannexin 1 Reduces the Tumorigenic Properties of Human Melanoma Cells. Cancers 2019, 11, 102.

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