A novel role of gap junction connexin46 protein to protect breast tumors from hypoxia (original) (raw)
Related papers
Journal of Biological Chemistry, 2011
Connexins are the transmembrane proteins that form gap junctions between adjacent cells. The function of the diverse connexin molecules is related to their tissue-specific expression and highly dynamic turnover. Although multiple connexins have been previously reported to compensate for each other's functions, little is known about how connexins influence their own expression or intracellular regulation. Of the three vertebrate lens connexins, two connexins, connexin43 (Cx43) and connexin46 (Cx46), show reciprocal expression and subsequent function in the lens and in lens cell culture. In this study, we investigate the reciprocal relationship between the expression of Cx43 and Cx46. Forced depletion of Cx43, by tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate, is associated with an up-regulation of Cx46 at both the protein and message level in human lens epithelial cells. An siRNA-mediated down-regulation of Cx43 results in an increase in the level of Cx46 prot...
Connexins and Gap Junctions in Mammary Gland Development and Breast Cancer Progression
Journal of Membrane Biology, 2007
The development and function of the mammary gland require precise control of gap junctional intercellular communication (GJIC). Here, we review the expression and function of gap junction proteins, connexins, in the normal mouse and human mammary gland. We then discuss the possible tumor-suppressive role of Cx26 and Cx43 in primary breast tumors and through the various stages of breast cancer metastasis and consider whether connexins or GJIC may actually promote tumorigenesis at some stages. Finally, we present in vitro data on the impact of connexin expression on breast cancer cell metastasis to the bone. We observed that Cx43 expression inhibited the invasive and migratory potentials of MDA-MB-231 breast cancer cells in a bone microenvironment, provided by the MC3T3-E1 mouse osteoblastic cell line. Expression of either Cx26 or Cx43 had no effect on MDA-MB-231 growth and adhesion under the influence of osteoblasts and did not result in regulation of osteogenic gene expression in these breast cancer cells. Furthermore, connexin-expressing MDA-MB-231 cells did not have an effect on the growth or differentiation of MC3T3-E1 cells. In summary, we conclude that connexin expression and GJIC are integral to the development and differentiation of the mammary gland. In breast cancer, connexins generally act as tumor suppressors in the primary tumor; however, in advanced breast tumors, connexins appear to act as both context-dependent tumor suppressors and facilitators of disease progression.
Connexin 43 mediated gap junctional communication enhances breast tumor cell diapedesis in culture
Breast cancer research : BCR, 2005
Metastasis involves the emigration of tumor cells through the vascular endothelium, a process also known as diapedesis. The molecular mechanisms regulating tumor cell diapedesis are poorly understood, but may involve heterocellular gap junctional intercellular communication (GJIC) between tumor cells and endothelial cells. To test this hypothesis we expressed connexin 43 (Cx43) in GJIC-deficient mammary epithelial tumor cells (HBL100) and examined their ability to form gap junctions, establish heterocellular GJIC and migrate through monolayers of human microvascular endothelial cells (HMVEC) grown on matrigel-coated coverslips. HBL100 cells expressing Cx43 formed functional heterocellular gap junctions with HMVEC monolayers within 30 minutes. In addition, immunocytochemistry revealed Cx43 localized to contact sites between Cx43 expressing tumor cells and endothelial cells. Quantitative analysis of diapedesis revealed a two-fold increase in diapedesis of Cx43 expressing cells compare...
Journal of Biomedical Science
Connexin, a four-pass transmembrane protein, contributes to assembly of gap junctions among neighboring cells and thus facilitates gap junctional intercellular communication (GJIC). Traditionally, the roles of connexins were thought to mediate formation of hemichannels and GJIC assembly for transportation of ions and small molecules. Many studies have observed loss of GJIC, due to reduced expression or altered cytoplasmic localization of connexins, in primary tumor cells. Connexins are generally considered tumor-suppressive. However, recent studies of clinical samples suggested a different role of connexins in that expression levels and membrane localization of connexins, including Connexin 43 (Cx43, GJA1) and Connexin 26 (Cx26, GJB2), were found to be enhanced in metastatic lesions of cancer patients. Cx43-and Cx26-mediated GJIC was found to promote cancer cell migration and adhesion to the pulmonary endothelium. Regulatory circuits involved in the induction of connexins and their functional effects have also been reported in various types of cancer. Connexins expressed in stromal cells were correlated with metastasis and were implicated in regulating metastatic behaviors of cancer cells. Recent studies have revealed that connexins can contribute to cellular phenotypes via multiple ways, namely 1) GJIC, 2) C-terminal tail-mediated signaling, and 3) cell-cell adhesion during gap junction formation. Both expression levels and the subcellular localization could participate determining the functional roles of connexins in cancer. Compounds targeting connexins were thus tested as potential therapeutics intervening metastasis or chemoresistance. This review focuses on the recent findings in the correlation between the expression of connexins and patients' prognosis, their roles in metastasis and chemoresistance, as well as the implications and concerns of using connexin-targeting drugs as anti-metastatic therapeutics. Overall, connexins may serve as biomarkers for cancer prognosis and as therapeutic targets for intervening metastasis and chemoresistance.
Role of connexin (gap junction) genes in cell growth control and carcinogenesis
Comptes Rendus de l'Académie des Sciences - Series III - Sciences de la Vie, 1999
Evidence is accumulating that connexin (Cx) genes form a family of tumor-suppressor genes. Our long-standing study revealed that, in almost all tumors, some abnormality in gap junction is observed, including loss or reduction of expression, aberrant localization of gap junction. In this study, we have examined the dominant-negative effects of mutant (prepared by site-directed mutagenesis) Cx43 constructs in C6 glioma cells, and of mutant Cx26 constructs in HeLa cells, on tumorigenicity. The mutant Cx43 A253V (Ala 253 to Val) inhibited the tumor-suppressive function exerted by wild-type Cx43 in C6 cells. Similarly, the mutant Cx26 P87L (Pro 87 to Leu) manifested dominant-negative inhibition of connexin-mediated cell growth control in HeLa cells. These results suggest that mutations of connexin genes can affect the tumor-suppressive function of gap junction and that gap junctional intercellular communication can be regulated by not only non-genotoxic but also genotoxic activities of environmental carcinogens.
Connexin mediates gap junction-independent resistance to cellular injury
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
Although gap junctions regulate essential processes during development and differentiation, the role of gap junctions in cell death is poorly understood. We demonstrate here that the forced expression of connexin 43 (Cx43), the main constituent of astrocytic gap junctions, protected against cell injury with a potency that was comparable with that from the expression of the proto-oncogene bcl2. The expression of two other members of the Cx family, Cx32 and Cx40, also increased the resistance to injury from exposures to calcium overload, oxidative stress, metabolic inhibition, tamoxifen, and UV irradiation, but not against staurosporine- and dexamethasone-mediated death. Surprisingly, the anti-death activity of connexin proteins was independent of gap junction channel function, because physical isolation or the pharmacological inhibition of coupling did not significantly increase cell death. Moreover, cells expressing nonfunctional mutant connexins also acquired a high resistance to i...
PLoS ONE, 2013
Connexin channels play a critical role in maintaining metabolic homeostasis and transparency of the lens. Mutations in connexin genes are linked to congenital cataracts in humans. The G143R missense mutation on connexin (Cx) 46 was recently reported to be associated with congenital Coppock cataracts. Here, we showed that the G143R mutation decreased Cx46 gap junctional coupling in a dominant negative manner; however, it significantly increased gap junctional plaques. The G143R mutant also increased hemichannel activity, inversely correlated with the level of Cx46 protein on the cell surface. The interaction between cytoplasmic loop domain and C-terminus has been shown to be involved in gating of connexin channels. Interestingly, the G143R mutation enhanced the interaction between intracellular loop and Cx46. Furthermore, this mutation decreased cell viability and the resistance of the cells to oxidative stress, primarily due to the increased hemichannel function. Together, these results suggest that mutation of this highly conserved residue on the cytoplasmic loop domain of Cx46 enhances its interaction with the C-terminus, resulting in a reduction of gap junction channel function, but increased hemichannel function. This combination leads to the development of human congenital cataracts.
Connexins in cancer: bridging the gap to the clinic
Oncogene, 2019
Gap junctions comprise arrays of intercellular channels formed by connexin proteins and provide for the direct communication between adjacent cells. This type of intercellular communication permits the coordination of cellular activities and plays key roles in the control of cell growth and differentiation and in the maintenance of tissue homoeostasis. After more than 50 years, deciphering the links among connexins, gap junctions and cancer, researchers are now beginning to translate this knowledge to the clinic. The emergence of new strategies for connexin targeting, combined with an improved understanding of the molecular bases underlying the dysregulation of connexins during cancer development, offers novel opportunities for clinical applications. However, different connexin isoforms have diverse channel-dependent and-independent functions that are tissue and stage specific. This can elicit both pro-and anti-tumorigenic effects that engender significant challenges in the path towards personalised medicine. Here, we review the current understanding of the role of connexins and gap junctions in cancer, with particular focus on the recent progress made in determining their prognostic and therapeutic potential.
Connexins: a junctional crossroad to breast cancer
The International Journal of Developmental Biology, 2011
The mammary gland presents a valuable model for developmental studies, spanning the embryonic stage through menarche to menopause. The dynamic remodeling of this gland is orchestrated by cellular heterogeneity, integrating mammogenic, systemic and local cues. Gap junctional intercellular communication provides pivotal cross talk of mammary epithelial cells with the surrounding cells and their local microenvironment. Connexins are involved in regulating normal and pathological mammary gland development, through channel-dependent and channelindependent roles. Modulation of the isoforms of connexins expressed, as well as their differential assembly into connexons and recruitment of a variety of associated partners, contributes to the complexity of signaling relayed at the membrane. This confers context-dependent functions of connexins at different stages of development and carcinogenesis. This review will summarize available knowledge about the functional dynamics of connexins and gap junctions in regulating normal mammary gland development and its pathophysiology.