Cancer Connectors: Connexins, Gap Junctions, and Communication

Frontiers in Oncology

Ofer Reizes¹  Maksim Sinyuk⁴  Erin E. Mulkearns-Hubert⁴  Justin Lathia⁵ 

[1] Case Comprehensive Cancer Center, Case Western University, Cleveland, OH, United States;Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, United States;Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, United States;Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States;Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States;

关键词: connexin;    gap junction;    intercellular communication;    hemichannels;    bystander effect;    cancer;   

DOI  :  10.3389/fonc.2018.00646

来源: DOAJ

【 摘 要 】

Despite concerted clinical and research efforts, cancer is a leading cause of death worldwide. Surgery, radiation, and chemotherapy have remained the most common standard-of-care strategies against cancer for decades. However, the side effects of these therapies demonstrate the need to investigate adjuvant novel treatment modalities that minimize the harm caused to healthy cells and tissues. Normal and cancerous cells require communication amongst themselves and with their surroundings to proliferate and drive tumor growth. It is vital to understand how intercellular and external communication impacts tumor cell malignancy. To survive and grow, tumor cells, and their normal counterparts utilize cell junction molecules including gap junctions (GJs), tight junctions, and adherens junctions to provide contact points between neighboring cells and the extracellular matrix. GJs are specialized structures composed of a family of connexin proteins that allow the free diffusion of small molecules and ions directly from the cytoplasm of adjacent cells, without encountering the extracellular milieu, which enables rapid, and coordinated cellular responses to internal and external stimuli. Importantly, connexins perform three main cellular functions. They enable direct gap junction intercellular communication (GJIC) between cells, form hemichannels to allow cell communication with the extracellular environment, and serve as a site for protein-protein interactions to regulate signaling pathways. Connexins themselves have been found to promote tumor cell growth and invasiveness, contributing to the overall tumorigenicity and have emerged as attractive anti-tumor targets due to their functional diversity. However, connexins can also serve as tumor suppressors, and therefore, a complete understanding of the roles of the connexins and GJs in physiological and pathophysiological conditions is needed before connexin targeting strategies are applied. Here, we discuss how the three aspects of connexin function, namely GJIC, hemichannel formation, and connexin-protein interactions, function in normal cells, and contribute to tumor cell growth, proliferation, and death. Finally, we discuss the current state of anti-connexin therapies and speculate which role may be most amenable for the development of targeting strategies.

【 授权许可】

Unknown