Connexin-related signaling in cell death: to live or let die?

Decrock, Elke; Vinken, Mathieu; Vuyst, Elke De; Krysko, Dmitri V.; D’Herde, Katharina; Vanhaecke, Tamara; Vandenabeele, Peter; Rogiers, Vera; Leybaert, Luc

doi:10.1038/cdd.2008.196

Cited by 231 publications

(293 citation statements)

References 199 publications

(291 reference statements)

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“…1,2 Gap junction-mediated intercellular communication also modulates apoptosis in a variety of systems, even though the effect may be anti-or proapoptotic, depending on the connexin isoform and the cell type. 3 We recently reported that mice lacking Connexin36 (Cx36), the sole connexin expressed in b-cells, 1,2 are sensitized to cytotoxic drugs and cytokines, whereas mice overexpressing Cx36 in b-cells are more resistant to these insults. 4 However, the molecular mechanism of this protection remains to be established.…”

mentioning

confidence: 99%

Connexin36 contributes to INS-1E cells survival through modulation of cytokine-induced oxidative stress, ER stress and AMPK activity

et al. 2013

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Cell-to-cell communication mediated by gap junctions made of Connexin36 (Cx36) contributes to pancreatic b-cell function. We have recently demonstrated that Cx36 also supports b-cell survival by a still unclear mechanism. Using specific Cx36 siRNAs or adenoviral vectors, we now show that Cx36 downregulation promotes apoptosis in INS-1E cells exposed to the pro-inflammatory cytokines (IL-1b, TNF-a and IFN-c) involved at the onset of type 1 diabetes, whereas Cx36 overexpression protects against this effect. Cx36 overexpression also protects INS-1E cells against endoplasmic reticulum (ER) stress-mediated apoptosis, and alleviates the cytokine-induced production of reactive oxygen species, the depletion of the ER Ca 2 þ stores, the CHOP overexpression and the degradation of the anti-apoptotic protein Bcl-2 and Mcl-1. We further show that cytokines activate the AMP-dependent protein kinase (AMPK) in a NO-dependent and ER-stress-dependent manner and that AMPK inhibits Cx36 expression. Altogether, the data suggest that Cx36 is involved in Ca 2 þ homeostasis within the ER and that Cx36 expression is downregulated following ER stress and subsequent AMPK activation. As a result, cytokine-induced Cx36 downregulation elicits a positive feedback loop that amplifies ER stress and AMPK activation, leading to further Cx36 downregulation. The data reveal that Cx36 plays a central role in the oxidative stress and ER stress induced by cytokines and the subsequent regulation of AMPK activity, which in turn controls Cx36 expression and mitochondria-dependent apoptosis of insulin-producing cells.

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confidence: 99%

Connexin36 contributes to INS-1E cells survival through modulation of cytokine-induced oxidative stress, ER stress and AMPK activity

et al. 2013

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“…Several groups have also observed increased cytotoxicity of cancer cells to a variety of chemotherapeutic agents such as doxorubicin, cisplatin, vinblastine, docetaxel, and BCNU in association with GJIC (reviewed in [5]). These enhanced chemotherapeutic drug effects were associated with reduced expression of bcl-2 and increased apoptosis, decreased expression of p-glycoprotein, lowered intracellular glutathione content, and gap junction-mediated transfer of apoptosis-inducing signals from damaged cells to neighbors.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, GJIC contributes to the radiation "bystander effect" in which signaling molecules and/or reactive oxygen species induce damage in neighboring, non-irradiated cells [21] [22]. In contrast, GJIC may also reduce drug, ischemic, and radiation-induced cytotoxicity possibly by cell-cell sharing of protective molecules like glutathione [5] [23]. Furthermore, these effects may not be due solely to GJIC.…”

Section: Discussionmentioning

confidence: 99%

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Gap Junctional Intercellular Communication Increases Cytotoxicity and Reduces Resistance to Hydroxyurea

Ruch¹,

Boucher²,

Gentry³

et al. 2014

JCT

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Background: Gap junctions enable small molecules to diffuse between adjacent cells and have been associated with greater cytotoxicity of radiation and anti-cancer drugs. We investigated whether this gap junctional intercellular communication (GJIC) affected the cytotoxicity of the classic ribonucleotide reductase (RR) inhibitor and anti-cancer agent, hydroxyurea (HU). Materials and Methods: We used GJIC-proficient and deficient, connexin 43-expressing WB rat liver epithelial cell lines. We compared HU toxicity by crystal violet assay, effects of the drug on deoxynucleotide pools by HPLC, and ability of GJIC to increase toxicity of HU-resistant cells through a bystander effect in co-culture experiments. Results: GJIC-proficient cells were three-to five-fold more sensitive (IC50 0.1 mM) to HU than GJIC-deficient derivatives (IC 50 0.3 -0.5 mM). This sensitivity depended upon GJIC because treatment of GJIC-proficient cells with the GJIC blocker oleamide decreased HU toxicity by approximately 60% -80% and restoration of GJIC in GJIC-deficient cells by stable transduction of connexin 32-encoding Gjb1 increased HU toxicity (IC 50 0.1 mM). The effects were not due to connexin expression per se or its localization since all cell lines expressed comparable quantities of connexin 43 that was localized to the plasma membrane. Also HU sensitivity was not related to differential effects on nucleotide metabolism in the cells. Thymidine triphosphate levels increased and deoxyadenosine triphosphate levels decreased similarly (15% -20%) in GJIC-proficient and deficient cells over 24 h of HU treatment. More importantly, when HU-resistant cells were co-cultured with sensitive cells, the resistant cells were killed only when GJIC was present. Conclusion: The data suggest that GJIC enhances cytotoxicity and decreases resistance to HU. These results may be important clinically if GJIC can be enhanced in drug-resistant cells.

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“…To date, at least 21 members of connexins proteins have been identified in mammalian. Certain connexins have been reported to have tumor suppressing effect, including connexin43, connexin32 and connexin26 (Tanaka et al, 2004;Fujimoto et al, 2005;Decrock et al, 2009). Connexin 26 is one of the most frequently investigated Connexin proteins which shows growth inhibition and induction of apoptosis (Connexins) (Tanaka et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Paris polyphylla Smith Extract Induces Apoptosis and Activates Cancer Suppressor Gene Connexin26 Expression

Jiao²,

Yao³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Connexin-related signaling in cell death: to live or let die?

Cited by 231 publications

References 199 publications

Connexin36 contributes to INS-1E cells survival through modulation of cytokine-induced oxidative stress, ER stress and AMPK activity

Connexin36 contributes to INS-1E cells survival through modulation of cytokine-induced oxidative stress, ER stress and AMPK activity

Gap Junctional Intercellular Communication Increases Cytotoxicity and Reduces Resistance to Hydroxyurea

Paris polyphylla Smith Extract Induces Apoptosis and Activates Cancer Suppressor Gene Connexin26 Expression

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