Gap junctional intercellular communication and connexin 43 expression in ovarian carcinoma

Umhauer, Sandra; Ruch, Randall J.; Fanning, James

doi:10.1016/s0002-9378(00)70135-9

Cited by 42 publications

(23 citation statements)

References 8 publications

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“…We and others have shown that Cx43 is undetectable in early stage human breast cancer tissue compared with adjacent normal tissue (Nicolson et al, 1988;Lee et al, 1992;Holden et al, 1997;Laird et al, 1999). Similar results are observed in other cancer tissues, such as ovarian cancer, lung cancer, and neuroblastomas (Albright et al, 1990;Tsai et al, 1996;Huang et al, 1999;Umhauer et al, 2000). This loss in Cx43 is believed to be among the earliest events by which transformed cells acquire independence from stimuli from neighboring cells.…”

supporting

confidence: 79%

Unexpected Induction of the Human Connexin 43 Promoter by the Ras Signaling Pathway Is Mediated by a Novel Putative Promoter Sequence

Carystinos¹,

Kandouz²,

Alaoui‐Jamali³

et al. 2003

Mol Pharmacol

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Connexin 43 (Cx43) is essential for survival and is tightly regulated at the transcriptional and post-transcriptional levels. A number of previous studies have demonstrated altered expression in malignant tissues, and in the presence of carcinogenic factors. We examined the effect of protooncogenes of Cx43 expression, and found no effect on Cx43 promoter activity in cells transformed with Src or erbB2. On the other hand, we identified and characterized a novel sequence that mediates Cx43 promoter regulation in cell lines engineered to overexpress H-Ras. Compared with wild-type NIH3T3 cells, both Cx43 mRNA and protein levels are increased in NIH3T3-Ras cells. The H-Rasϩ cells also have enhanced Cx43 promoter activation, which is inhibited by the MEK1 inhibitor 2Ј-amino-3Ј-methoxyflavone (PD98059), suggesting that Ras-mediated Cx43 overexpression is via the mitogen activated protein kinase kinase/extracellular signal-regulated pathway. Deletion analysis of the Cx43 promoter revealed a 200-bp region downstream of the Cx43 transcription start site as the minimal sequence essential for the Ras-mediated Cx43 up-regulation. Using this 200-base pair fragment in electrophoretic mobility shift assays, we identified one main protein complex that binds efficiently and is more abundant in nuclear extracts from NIH3T3-Ras and MCF7-Ras cells compared with their matched controls. This complex selectively recognizes a consensus sequence, AGTTCAATCA, located at positions ϩ149 to ϩ158 of the Cx43 promoter. Supershift assays identified the 90-kDa heat shock protein (HSP90) and c-Myc as constituents of this DNA-binding complex. Treatment of cells with the HSP90 inhibitor geldanamycin resulted in repression of the Cx43 promoter activity, and inhibits binding of the complex to the Cx43 promoter. Coimmunoprecipitation studies confirmed the interaction between endogenous HSP90 and c-Myc. This study provides evidence that the transcriptional up-regulation of Cx43 by Ras-Raf-MAPK is mediated via the interaction of a novel Cx43 promoter element with a protein complex that contains both HSP90 and c-Myc.

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supporting

confidence: 79%

Unexpected Induction of the Human Connexin 43 Promoter by the Ras Signaling Pathway Is Mediated by a Novel Putative Promoter Sequence

Carystinos¹,

Kandouz²,

Alaoui‐Jamali³

et al. 2003

Mol Pharmacol

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“…In larger lung tumors, Cx32 and Cx40 are down-regulated, but Cx37, Cx43, and Cx45 are expressed (Isakson et al, 2001a(Isakson et al, ,b, 2003Udaka et al, 2006). In other cases, such as ovarian adenocarcinomas and cervical cancer, GJIC is dramatically reduced (Hanna et al, 1999;Umhauer et al, 2000;Aasen et al, 2005;Gershon et al, 2008). In this situation, because GJIC is already essentially absent, the effect of platinating reagents described in the present study would not occur, but in the former cases, the effect on the efficacy of the drugs due to effects on GJIC could occur.…”

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confidence: 59%

Cisplatin and Oxaliplatin Inhibit Gap Junctional Communication by Direct Action and by Reduction of Connexin Expression, Thereby Counteracting Cytotoxic Efficacy

Wang

You²,

Yuan³

et al. 2010

J Pharmacol Exp Ther

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Cisplatin [cis-diamminedichloroplatinum(II)]/oxaliplatin [1,2-diamminocyclohexane(trans-1)oxolatoplatinum(II)] toxicity is enhanced by functional gap junctions between treated cells, implying that inhibition of gap junctions may decrease cytotoxic activity of these platinum-based agents. This study investigates the effect of gap junction modulation by cisplatin/oxaliplatin on cytotoxicity in a transformed cell line. The effects were explored using junctional channels expressed in transfected HeLa cells and purified hemichannels. Junctional channels showed a rapid, dose-dependent decrease in dye coupling with exposure to cisplatin/oxaliplatin. With longer exposure, both compounds also decreased connexin expression. Both compounds inhibit the activity of purified connexin hemichannels, over the same concentration range that they inhibit junctional dye permeability, demonstrating that inhibition occurs by direct interaction of the drugs with connexin protein. Cisplatin/oxaliplatin reduced the clonogenic survival of HeLa cells at low density and high density in a dose-dependent manner, but to a greater degree at high density, consistent with a positive effect of gap junctional intercellular communication (GJIC) on cytotoxicity. Reduction of GJIC by genetic or pharmacological means decreased cisplatin/oxaliplatin toxicity. At low cisplatin/oxaliplatin concentrations, where effects on connexin channels are minimal, the toxicity increased with increased cell density. However, higher concentrations strongly inhibited GJIC, and this counteracted the enhancing effect of greater cell density on toxicity. The present results indicate that inhibition of GJIC by cisplatin/ oxaliplatin decreases their cytotoxicity. Direct inhibition of GJIC and reduction of connexin expression by cisplatin/oxaliplatin may thereby compromise the effectiveness of these compounds and be a factor in the development of resistance to this class of chemotherapeutic agents.

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“…Interestingly, loss or dysfunction of gap junctions appears to be important in allowing cancer cells to escape growth regulation, as has been shown by the loss of Cx43 expression in human ovarian carcinoma cells (44). In consequence, Cx43 is an interesting factor to analyze in luteoma sections.…”

Section: Discussionmentioning

confidence: 98%

Development of an experimental ovarian tumor: immunocytochemical analysis

Sorianello

Fritz

Beyer

et al. 2002

European Journal of Endocrinology

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Objective: The aim of the present work was to study whether immunocytochemical parameters present in the normal ovary were altered after tumor development under high gonadotropin levels. Methods: Ovarian tumors (luteoma): castrated female rats had an ovary grafted into the spleen; tumors were left to develop for 1, 2, 3 or 7 months. The presence of apoptotic cells (TUNEL method) and the expression of proliferating cell nuclear antigen (PCNA), gap junction protein (Cx43), steroidogenic acute regulatory protein (StAR), aromatase and synaptosome-associated protein of 25 kDa (SNAP-25) were determined by immunocytochemistry. Some of these findings were confirmed by RT-PCR (Cx43, StAR, SNAP-25). Inhibin subunit mRNAs were investigated by Northern blot. Results: PCNA staining of tumors was mainly found in granulosa cells of transforming follicles and was absent from luteinized follicles. A nearly complete absence of apoptosis was observed. Cx43 was mainly found in follicles, while it was very weakly expressed or absent in luteinized follicles. StAR protein expression, indicating active steroidogenesis, was demonstrated only in luteinized follicles and in thecal cells, but was absent from granulosa cells. Aromatase immunoreactivity was very intense in granulosa and also present in luteal cells. Membrane-associated and cytoplasmic SNAP-25 immunostaining was determined in patches of endocrine cells in the follicles, as well as in the luteinized follicles. The expression of mRNAs for Cx43, StAR and SNAP-25 (RT-PCR) and inhibin subunits (Northern blots) were confirmed in 1-, 3-and 7-month-old tumors. Conclusions: These results indicated that luteoma most likely develop from unruptured follicles by hypertrophy and proliferation of follicular cells. Circulating gonadotropins seem to play a fundamental role in maintaining the expression of proteins typically expressed in normal ovary, while avoiding apoptosis in this tissue.

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Gap junctional intercellular communication and connexin 43 expression in ovarian carcinoma

Cited by 42 publications

References 8 publications

Unexpected Induction of the Human Connexin 43 Promoter by the Ras Signaling Pathway Is Mediated by a Novel Putative Promoter Sequence

Unexpected Induction of the Human Connexin 43 Promoter by the Ras Signaling Pathway Is Mediated by a Novel Putative Promoter Sequence

Cisplatin and Oxaliplatin Inhibit Gap Junctional Communication by Direct Action and by Reduction of Connexin Expression, Thereby Counteracting Cytotoxic Efficacy

Development of an experimental ovarian tumor: immunocytochemical analysis

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