Differential effect of subcellular localization of communication impairing gap junction protein connexin43 on tumor cell growth in vivo

Krutovskikh, Vladimir; Troyanovsky, Sergey M.; Piccoli, C.; Tsuda, Hiroyuki; Asamoto, Makoto; Yamasaki, Hideo

doi:10.1038/sj.onc.1203340

Cited by 85 publications

(60 citation statements)

References 36 publications

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“…As reported (Huang et al, 1998;Krutovskikh et al, 2000), the ability of U2OS cells to form colonies in soft agar (Figure 1e) and tumors in nude mice ( Figure 1f) signi®cantly decreased in Cx43-transfected cells compared with the parental and vector-transfected cells. These data suggest that expression of Cx43 inhibited the tumorigenicity of U2OS cells.…”

Section: Restoration Of Gjic and Inhibition Of Tumorigenicity Of U2osmentioning

confidence: 56%

“…One is linked to the Cx-mediated GJIC function, in which putative growth inhibitory factors are assumed to di use through the GJ channels and then induce the growth inhibition (Loewenstein, 1979;Mehta et al, 1986;Cornil et al, 1991;Martin et al, 1991;Zhu et al, 1992). The other suggests that the Cx proteins themselves may show some GJIC-independent biological roles in inhibiting the tumor cell growth (Bradshaw et al, 1993;Chen et al, 1995;Du¯ot-Dancer et al, 1997;Statuto et al, 1997;Omori and Yamasaki, 1998;Krutovskikh et al, 2000). However, the precise mechanisms remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…It has shown wide inhibitory e ects on tumor growth of various cell lines (Zhu et al, 1992;Chen et al, 1995;Mesnil et al, 1995;Proulx et al, 1997;Huang et al, 1998;Omori and Yamasaki, 1998;Krutovskikh et al, 2000). We ®rst illustrate that forced expression of Cx43 inhibited the proliferation of U2OS cells through a reduced rate of G1/S transition of the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

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Connexin43 suppresses proliferation of osteosarcoma U2OS cells through post-transcriptional regulation of p27

et al. 2001

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Many lines of evidence indicate that connexin genes expressing gap junction (GJ) proteins inhibit tumor cell proliferation. However, the precise molecular mechanisms remain unclear. In this study, we show that overexpression of connexin43 (Cx43) suppressed proliferation of human osteosarcoma U2OS cells through inhibition of the cell cycle transition from G1 to S phase. This inhibition was attributed to a signi®cant accumulation of the hypophosphorylated retinoblastoma (Rb) protein, which was causally related to decreases in the kinase activities of cyclin-dependent kinases (CDKs) 2 and 4. Enforced Cx43 expression markedly increased the level of the CDK inhibitor p27. This increase resulted from an increased synthesis and a reduced degradation of the p27 proteins, but not in¯uence of the p27 mRNA. Moreover, we show that the Cx43-modulated GJ function was the main contributor to the elevation in p27 levels, in which cAMP was involved. These data suggest that Cx43 appears to inhibit proliferation of U2OS cells by increasing the levels of p27 proteins via post-transcriptional regulatory mechanisms. Oncogene (2001) 20, 4138 ± 4149.

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Section: Restoration Of Gjic and Inhibition Of Tumorigenicity Of U2osmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Connexin43 suppresses proliferation of osteosarcoma U2OS cells through post-transcriptional regulation of p27

et al. 2001

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“…Much remains to be learned about how the specific combination of connexins facilitates tissue interactions, but it is clear, again, that generalizations should be avoided, as the expression patterns (and probably the function) of connexins are tissue dependent and change during tumour progression 17,18 . For example, some breast cancer cells upregulate connexin 32 (Cx32) 19 , but loss of Cx32 contributes to hepatocellular carcinoma 20,21 ; Cx43 inhibits tumorigenicity of lung, cervical and bladder carcinoma cells [22][23][24] , but has no effect on squamous cell carcinomas 25 ; and other connexins can facilitate cell adhesion during metastasis 26 .…”

Section: Box 1 Epithelial Cell Polarity and Tumorigenesis In Drosophilamentioning

confidence: 99%

Putting tumours in context

2001

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The interactions between cancer cells and their micro-and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.Under normal conditions, ORGANS are made up of TISSUES that exchange information with other cell types via cell-cell contact, cytokines and the EXTRACELLULAR MATRIX (ECM). The ECM, which is produced by collaboration between STROMAL fibroblasts and EPITHELIAL cells, provides structural scaffolding for cells, as well as contextual information. The endothelial vasculature provides nutrients and oxygen, and cells of the immune system combat pathogens and remove apoptotic cells. Epithelial cells associate into intact, polarized sheets. These tissues communicate through a complex network of interactions: physically, through direct contact or through the intervening ECM, and biochemically, through both soluble and insoluble signalling molecules. In combination, these interactions provide the information that is necessary to maintain cellular differentiation and to create complex tissue structures.Occasionally, the intercellular signals that define the normal context become disrupted. Alterations in epithelial tissues can lead to movement of epithelial sheets and proliferationfor example, after activation of mesenchymal fibroblasts due to wounding. Normally, these conditions are temporary and reversible, but when inflammation is sustained, an escalating feedback loop ensues. Under persistent inflammatory conditions, continual upregulation of enzymes such as matrix metalloproteinases (MMPs) by stromal fibroblasts can disrupt the ECM, and invading immune cells can overproduce factors that promote abnormal proliferation.As this process progresses, the normal organization of the organ is replaced by a functional disorder (FIG. 1). If there are pre-existing epithelial cells within this changing context that possess tumorigenic potential, they can start to proliferate. Alternatively, the abnormal An innate anticancer mechanismAn important feature of the normal stromal context is the generation and maintenance of epithelial-cell polarity. Epithelial cells receive a variety of orientational cues from the environment that help them establish cellular apical and basal surfaces and to maintain the differentiated state. Loss of polarity has been shown to lead to increased cell proliferation and tumorigenesis (BOX 1). The basal surface of epithelial cells associates with the BASEMENT MEMBRANE, a specialized form of ECM that provides both structural support and polarization signals to epithelia. The basement membrane is a dynamic structure. Changes in its composition lead to changes in cell shape and behaviour 1 , altered binding affinity or cellular distribution of cell-surface receptors 2 , and cellu...

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“…Krutovskikh et al [30] discovered that subcellular localization of Cx43 in tumour cells could play a role in the regulation of tumour growth. Recently, Olbina et al [31] showed that changes in protein sequence of the second extracellular region of Cx43 prevent incorporation of the protein into the plasma membrane, but do not decrease its ability to inhibit the growth of tumour cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

Expression of connexin 26 in endometrial adenocarcinoma--analysis of correlations with some anatomoclinical features.

Lesniewicz

Kańczuga‐Koda²,

Baltaziak³

et al. 2008

Folia Histochem Cytobiol.

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Abstract:Alterations of gap junctional intercellular communication appear to play a role in the development and progression of cancer. Gap junction channel is composed of two connexons -hexameric units formed of transmembrane proteins called connexins (Cxs). The aim of the study was to evaluate the expression and localization of Cx26 in 73 cases of endometrial cancers and to estimate the relationships between expression of this protein and selected anatomoclinical features. The control group consisted of 20 sections of normal endometrium in various menstrual cycle phases, obtained from premenopausal women. In the normal endometrium punctate, membrane-associated immunoreactivity for Cx26 was observed. 54 of 73 endometrial cancers showed Cx26 expression, but 46/54 (85%) immunopositive sections revealed cytoplasmic localization for Cx26 with granular or occasionally diffuse immunostaining pattern. In addition, part of Cx26-positive tumours showed mixed: cytoplasmic and membranous staining pattern and focally also nuclear or perinuclear immunostaining was present. In 21/54 (39%) of Cx26-positive cases weak staining pattern was seen, however in 33/54 (61%) cancers strong reaction was noted. We did not find relationship between Cx26 expression and patients' age, histological type of cancer and histological grade, nevertheless we observed positive association between Cx26 expression and tumour size (p=0.037). In conclusion, our results suggest that transformed malignant cells continue to produce Cx26, which are probably not assembled into functional gap junction channels, but could still play other roles in endometrial cancer cells.

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Differential effect of subcellular localization of communication impairing gap junction protein connexin43 on tumor cell growth in vivo

Cited by 85 publications

References 36 publications

Connexin43 suppresses proliferation of osteosarcoma U2OS cells through post-transcriptional regulation of p27

Connexin43 suppresses proliferation of osteosarcoma U2OS cells through post-transcriptional regulation of p27

Putting tumours in context

Expression of connexin 26 in endometrial adenocarcinoma--analysis of correlations with some anatomoclinical features.

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