Intercellular Communication and the Control of Tissue Growth: Lack of Communication between Cancer Cells

Loewenstein, Werner R.; Kanno, Yoshinobu

doi:10.1038/2091248a0

Cited by 386 publications

(220 citation statements)

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“…1 Intercellular communication through gap junction (GJIC) plays a significant role in maintaining tissue homeostasis by exchanging small molecules, such as sugars, nucleotides, and second messengers, which has long been proposed as a mechanism to regulate growth control, development and differentiation. 3 Dysfunctional GJIC has been also recognized as being involved in carcinogenesis. 3,4 It has been showed that down-regulation of connexin 43 (Cx43) expression and dysfunctional GJIC occur in nasopharyngeal carcinomas tissues and cells, [5][6][7][8] suggesting that dysfunctional GJIC plays a key role in naopharyngeal carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of connexin 43 in nasopharyngeal carcinoma cells is related to promoter methylation

et al. 2007

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Summary Down-regulation of Cx43 expression had been shown to occur in nasopharyngeal carcinoma cells. The present study was undertaken to estimate if methylation of the promoter region in Cx43 gene was responsible for the repression of Cx43 expression in the CNE-1 nasopharyngeal carcinoma cells. Calcein transfer and lucifer yellow transfer were detected to evaluate gap junction intercellular communication (GJIC) in CNE-1 cells. It was found that the control CNE-1 cells showed no fluorescent dye transfer. After treatment with DNA methyltransferase inhibitor 5-aza-CdR, fluorescent dye transfer between cells became obvious. RT-PCR and Western blot were performed to determine the expression of Cx43 gene. The control CNE-1 cells showed a low expression level of Cx43, whereas 5-aza-CdR-treated CNE-1 cells showed an enhanced level of Cx43 expression. Methylation-sensitive restriction enzyme and PCR analysis showed that the methylation of the Cx43 gene promoter region occurred in CNE-1 cells. In addition, treatment with 5-aza-CdR inhibited the growth (including anchorage-independent growth) of CNE-1 cells, and resulted in an accumulation of cells in G0/G1 phase. These results indicate the promoter methylation as an important role in inactivation of Cx43 in CNE-1 cells.

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Section: Introductionmentioning

confidence: 99%

“…3 Dysfunctional GJIC has been also recognized as being involved in carcinogenesis. 3,4 It has been showed that down-regulation of connexin 43 (Cx43) expression and dysfunctional GJIC occur in nasopharyngeal carcinomas tissues and cells, [5][6][7][8] suggesting that dysfunctional GJIC plays a key role in naopharyngeal carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of connexin 43 in nasopharyngeal carcinoma cells is related to promoter methylation

et al. 2007

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“…This exchange process, termed gap-junctional intercellular communication (GJIC) (Loewenstein and Kanno 1966;Civitelli 2008), occurs through channels comprising connexin proteins (Cx) (Willecke et al 2002) that span the plasma membranes of adjacent cells and facilitate the selective passage of water-soluble molecules (< 1.2 kDa), such as ions, nucleotides, cellular messengers (cAMP and inositol 1,4,5-triphosphate), and secondary metabolites (Civitelli 2008).…”

Section: Introductionmentioning

confidence: 99%

Delayed Osteoblastic Differentiation and Bone Development in Cx43 Knockout Mice

et al. 2011

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GJA1 gene (Connexin43, also known as Cx43) is the most abundant gap junction protein isoform in animal cells and is associated with bone development in embryos. The objective of the present work was to evaluate in vivo osteal development in GJA1-deficient fetal mice through determination of the histological and molecular alterations induced by partial or total deletion of the GJA1 gene. Heterozygous C57BL/6 mice (HT) harboring a null mutation of the GJA1 gene were mated, and pregnant females were submitted to euthanasia and Caesarean section from 12.5 to 19.5 days post coitum (dpc). HT (GJA1 þ/-) and homozygous (GJA1 -/-) knockout (KO) mutants and wild-type (WT) fetuses were identified by polymerase chain reaction (PCR), and development curves were constructed on the basis of fetus weight and crown-rump length. Histopathological, histochemical, and realtime PCR analyses were performed in order to assess the expression of markers associated with bone development, namely, osteocalcin, osteopontin, alkaline phosphatase, RUNX2, GJA1, GJC1 (Cx45), and GJA3 (Cx46). HT and KO fetuses exhibited delays in the differentiation of osteoblasts and, consequently, in bone development in comparison with the WT group. Additionally, less deposition of mineralized and osteoid matrix was observed in GJA1-deficient fetuses. Bone development in KO fetuses was delayed through the moment of birth, but in HT animals the delay only extended until 17.5 dpc, following which development was normalized. The expression of genes coding for osteocalcin, osteopontin, alkaline phosphatise, and RUNX2 were also delayed in GJA1-deficient fetuses. Animals that exhibited a lower expression of GJA1 presented delayed expression of the GJC1 and GJA3 genes and their corresponding protein products in the bone tissue. The results of the present study contribute to our understanding of the function of GJA1 during bone development and suggest that GJC1 could play a role in restoring intercellular communication in GJA1-deficient mice.

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“…Loewenstein and Kanno (1) were first to observe a decrease in gap junctional intercellular communication (GJIC) 1 in tumor cells when compared with their nontumorigenic counterpart cells. Since then, many tissues and cell lines have been analyzed in which the hypothesis of GJIC down-regulation in tumor tissues is upheld (2)(3)(4).…”

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confidence: 99%

CCN3 (NOV) Interacts with Connexin43 in C6 Glioma Cells

Bechberger

Ozog

et al. 2004

Journal of Biological Chemistry

146

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Many tumor cells exhibit aberrant gap junctional intercellular communication, which can be restored by transfection with connexin genes. We have previously discovered that overexpression of connexin43 (Cx43) in C6 glioma cells not only reduces proliferation but also leads to production of soluble growth-inhibitory factors. We identified that several members of the CCN (Cyr61/ connective tissue growth factor/nephroblastoma-overexpressed) family are up-regulated following Cx43 expression, including CCN3 (NOV). We now report evidence for an association between CCN3 and Cx43. Western blot analysis demonstrated that the 48-kDa fulllength CCN3 protein was present in the lysate and conditioned medium of growth-suppressed C6-Cx43 cells, as well as primary astrocytes, but not in C6 parental and human glioma cells. Immunocytochemical examination of CCN3 revealed diffuse localization in parental C6 cells, whereas transfection of C6 cells with Cx43 (C6-Cx43) or with a modified Cx43 tagged to green fluorescent protein on its C terminus (Cx43-GFP) resulted in punctate staining, suggesting that CCN3 co-localizes with Cx43 in plaques at the plasma membrane. In cells expressing a C-terminal truncation of Cx43 (Cx43⌬244 -382), this co-localization was lost. Glutathione S-transferase pull-down assay and co-immunoprecipitation demonstrated that CCN3 was able to physically interact with Cx43. In contrast, CCN3 was not found to associate with Cx43⌬244 -382. Similar experiments revealed that CCN3 did not co-localize or associate with other connexins, including Cx40 or Cx32. Taken together, these data support an interaction of CCN3 with the C terminus of Cx43, which could play an important role in mediating growth control induced by specific gap junction proteins.

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Intercellular Communication and the Control of Tissue Growth: Lack of Communication between Cancer Cells

Cited by 386 publications

References 10 publications

Downregulation of connexin 43 in nasopharyngeal carcinoma cells is related to promoter methylation

Downregulation of connexin 43 in nasopharyngeal carcinoma cells is related to promoter methylation

Delayed Osteoblastic Differentiation and Bone Development in Cx43 Knockout Mice

CCN3 (NOV) Interacts with Connexin43 in C6 Glioma Cells

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