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https://hdl.handle.net/10316/105851
Title: | Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells | Authors: | Tishchenko, Alexander Azorín, Daniel D. Vidal-Brime, Laia Muñoz, María José Arenas, Pol Jiménez Pearce, Christopher Girão, Henrique Ramón Y Cajal, Santiago Aasen, Trond |
Keywords: | connexin 43; gap junctions; cancer; intercellular communication; breast cancer; cell signaling; tunneling nanotubes; cell–cell communication; tumor microtubes | Issue Date: | 29-Sep-2020 | Publisher: | MDPI | Project: | Fundación Científica Asociación Española Contra el Cáncer (IDEAS SEMILLA AECC 2020/IDEAS20033PUIG) Instituto de Salud Carlos III, grants PI16/00772 and CPII16/00042 co-financed by the European Regional Development Fund (ERDF) and Instituto de Salud Carlos III, grants PI16/00772 Instituto de Salud Carlos III grant PI16/00772 co-financed by the European Regional Development Fund (ERDF). PAC “NETDIAMOND” POCI-01-0145-FEDER-016385 HealthyAging2020 CENTRO-01-0145-FEDER-000012-N2323 POCI-01-0145-FEDER-007440, CENTRO-01-0145-FEDER-032179 CENTRO-01-0145-FEDER-032414, POCI-01-0145-FEDER-022122 FCTUID/NEU/04539/2013 UID/NEU/04539/2019 UIDB/04539/2020 UIDP/04539/2020 |
Serial title, monograph or event: | Cancers | Volume: | 12 | Issue: | 10 | Abstract: | Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and thin membrane projections that connect cells, facilitating the exchange of not only small molecules, but also larger proteins, organelles, bacteria, and viruses. Typically, TNTs exhibit increased formation under conditions of cellular stress and are more prominent in cancer cells, where they are generally thought to be pro-metastatic and to provide growth and survival advantages. Cx43 has been described in TNTs, where it is thought to regulate small molecule diffusion through gap junctions. Here, we developed a high-fidelity CRISPR/Cas9 system to knockout (KO) Cx43. We found that the loss of Cx43 expression was associated with significantly reduced TNT length and number in breast cancer cell lines. Notably, secreted factors present in conditioned medium stimulated TNTs more potently when derived from Cx43-expressing cells than from KO cells. Moreover, TNT formation was significantly induced by the inhibition of several key cancer signaling pathways that both regulate Cx43 and are regulated by Cx43, including RhoA kinase (ROCK), protein kinase A (PKA), focal adhesion kinase (FAK), and p38. Intriguingly, the drug-induced stimulation of TNTs was more potent in Cx43 KO cells than in wild-type (WT) cells. In conclusion, this work describes a novel non-canonical role for Cx43 in regulating TNTs, identifies key cancer signaling pathways that regulate TNTs in this setting, and provides mechanistic insight into a pro-tumorigenic role of Cx43 in cancer. | URI: | https://hdl.handle.net/10316/105851 | ISSN: | 2072-6694 | DOI: | 10.3390/cancers12102798 | Rights: | openAccess |
Appears in Collections: | I&D ICBR - Artigos em Revistas Internacionais I&D CIBB - Artigos em Revistas Internacionais |
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