Upregulation of gap junctional intercellular communication and connexin 43 expression by cyclic-AMP and all- trans -retinoic acid is associated with glutathione depletion and chemosensitivity in neuroblastoma cells

Carystinos, George D.; Alaoui‐Jamali, Moulay A.; Phipps, J.; Yen, Lily; Batist, Gerald

doi:10.1007/s002800000231

Cited by 45 publications

(33 citation statements)

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“…A vast bulk of evidence has provided support to the view that vitamin A and carotenoids play protective roles in tumor promotion and progression (36)(37)(38)(39). However, the full range of the biological effects of vitamin A (ROL) and its derivatives, the retinoids remains incomplete.…”

Section: Discussionmentioning

confidence: 99%

Influence of a 50 Hz magnetic field and of all-trans‑retinol on the proliferation of human cancer cell lines

Trillo

2012

Int J Oncol

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Abstract. In vitro exposure to power frequency magnetic fields (MF) has been reported to influence cell proliferation and differentiation. However, the nature of the response of different human cancer cell types to these fields has not been sufficiently characterized. The present work investigates the response of two proliferating human cell lines of neuroblastoma (NB69) and hepatocarcinoma (HepG2) to a 42 h, intermittent treatment with a weak, 100 µT, 50 Hz MF, alone or in combination with 0.5 µM all-trans-retinol (ROL), a retinoid currently applied in oncostatic therapies. In each experimental replicate the cell samples were submitted to one of the following treatment combinations: MF+/ROL+, MF+/ ROL-, MF-/ROL+ or MF-/ROL-. The proliferative response was determined by cell counting (Trypan blue exclusion), BrdU incorporation and by spectrophotometric analysis of total protein and DNA content. The results show that when administered separately, the two treatments, MF and ROL, significantly enhanced cell proliferation in both cell lines. In NB69 simultaneous administration of MF and ROL induced an additive effect on cell proliferation, associated to increased DNA content. By contrast, in HepG2 the ROL-induced cell proliferation and increased protein content were partially blocked by simultaneous exposure to MF. Taken together, these data show that both agents, a weak MF and ROL at a low concentration, induce proliferative responses in the two assayed human cell lines. However, significant differences were observed between the responses of the two cellular species to the combined treatment with ROL and MF, indicating that the mechanisms underlying the cellular response to each of the two agents can mutually interact in a manner that is cell type-specific.

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Section: Discussionmentioning

confidence: 99%

Influence of a 50 Hz magnetic field and of all-trans‑retinol on the proliferation of human cancer cell lines

Trillo

2012

Int J Oncol

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“…Indeed, we and others have shown that gene therapy using sst2 as a tumor suppressor gene exerts antitumoral effects on experimental pancreatic cancers (6,58). On the other hand, through the mediation of a strong by-stander effect, gap junctions are known to render tumors much more sensitive to common chemotherapeutic compounds (5,54,55). Then, in addition to its own antitumoral effect, sst2 may also sensitize pancreatic cancers to conventional chemotherapy through a gap junction-mediated by-stander effect.…”

Section: Discussionmentioning

confidence: 99%

Restoration of Functional Gap Junctions through Internal Ribosome Entry Site-Dependent Synthesis of Endogenous Connexins in Density-Inhibited Cancer Cells

Lahlou

Fanjul

Pradayrol

et al. 2005

Molecular and Cellular Biology

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Gap junctions are composed of connexins and are critical for the maintenance of the differentiated state. Consistently, connexin expression is impaired in most cancer cells, and forced expression of connexins following cDNA transfection reverses the tumor phenotype. We have found that the restoration of density inhibition of human pancreatic cancer cells by the antiproliferative somatostatin receptor 2 (sst2) is due to overexpression of endogenous connexins Cx26 and Cx43 and consequent formation of functional gap junctions. Immunoblotting along with protein metabolic labeling and mRNA monitoring revealed that connexin expression is enhanced at the level of translation but is not sensitive to the inhibition of cap-dependent translation initiation. Furthermore, we identified a new internal ribosome entry site (IRES) in the Cx26 mRNA. The activity of Cx26 IRES and that of the previously described Cx43 IRES are enhanced in density-inhibited cells. These data indicate that the restoration of functional gap junctions is likely a critical event in the antiproliferative action of the sst2 receptor. We further suggest that the existence of IRESes in connexin mRNAs permits connexin expression in density-inhibited or differentiated cells, where cap-dependent translation is generally reduced.

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“…The expression of Cx43 in gap junction-deficient tumor cell lines has been well documented as a means of reestablishing several aspects of growth control (43). More recently, it has been shown that increased Cx43 enhances chemosensitivity in several cancer models (24,25). These studies used a variety of pharmacologic approaches to increase Cx43.…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 99%

“…Western Blot Cells were lysed in Tris-Cl buffer (pH 8.0) containing 0.5 mmol/L phenylmethylsulfonyl fluoride, 60 mmol/L KCl, 1 mmol/L EDTA, 1 mmol/L DTT, 0.5% NP40, 0.01 mg/mL leupeptin, and 0.01 mg/mL aprotinin as previously indicated (25). Equal amounts of protein were subjected to SDS-PAGE.…”

Section: Cell Cultures and Stable Clonesmentioning

confidence: 99%

“…It has been established that Cx43 plays an integral role in tumorigenesis, and we have shown a loss of Cx43 protein in breast cancer compared with normal adjacent tissue (23). Furthermore, an increase in sensitivity to common chemotherapeutic agents has been shown following the reexpression of Cx43 in human cancers (24,25), which suggests that understanding the regulation of Cx43 is of importance for future cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

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Connexin43 pseudogene in breast cancer cells offers a novel therapeutic target

Bier

Oviedo-Landaverde

Zhao

et al. 2009

Molecular Cancer Therapeutics

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Connexin43 (Cx43) is often deregulated in breast cancer tissue compared with normal adjacent tissue. Stable reexpression of Cx43 in cancer slows growth and renders the cells more sensitive to cytotoxic chemotherapeutics. Pseudogenes are often considered nonfunctional copies of DNA. The Cx43 pseudogene (ΨCx43) possesses all the features of an expressed gene and is exclusively transcribed in breast cancer cell lines and not in normal cells. ΨCx43 can be translated in vivo, and its protein exhibits growth-suppressive behavior similar to Cx43. We showed that ΨCx43 binds to the polyribosomes in breast cancer cells and that exogenous expression of ΨCx43 induces translational inhibition of Cx43. Furthermore, ΨCx43 is translated and binds more efficiently to the translational machinery than does Cx43 in an in vitro system. Following knockdown of ΨCx43 in breast cancer cells, we observed an increase in Cx43 RNA and protein. This results in increased cellular sensitivity to cytotoxic chemotherapy. Our results show that ΨCx43 acts as a posttranscriptional regulator of Cx43 in breast cancer cells, and that this represents an example of the regulation of genes by pseudogenes with potential therapeutic implications in cancer. [Mol Cancer Ther 2009;8(4):786-93]

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Upregulation of gap junctional intercellular communication and connexin 43 expression by cyclic-AMP and all- trans -retinoic acid is associated with glutathione depletion and chemosensitivity in neuroblastoma cells

Abstract: This study suggests that GJIC plays a role in cellular drug resistance, and highlights the potential use of GJIC modulators in combination with chemotherapy. Also, this is the first study exploring the ability of both db-cAMP and tRA to enhance cell chemosensitivity.

Cited by 45 publications

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Influence of a 50 Hz magnetic field and of all-trans‑retinol on the proliferation of human cancer cell lines

Influence of a 50 Hz magnetic field and of all-trans‑retinol on the proliferation of human cancer cell lines

Restoration of Functional Gap Junctions through Internal Ribosome Entry Site-Dependent Synthesis of Endogenous Connexins in Density-Inhibited Cancer Cells

Connexin43 pseudogene in breast cancer cells offers a novel therapeutic target

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