Connexin43 increases the sensitivity of prostate cancer cells to TNFα-induced apoptosis

Abstract

To examine the effects of increased expression of connexin43 (Cx43) upon cell viability and response to cytotoxic agents, we expressed Cx43 in LNCaP and PC3 prostate cancer cells by infection with a recombinant adenovirus (Ad-Cx43). Infection with Ad-Cx43 led to the formation of Cx43-containing gap junction plaques at appositional membranes and increased Lucifer Yellow transfer in LNCaP cells, but not in PC3 cells. The increased intercellular communication was blocked by co-infection with an adenovirus containing a dominant-negative Cx43 (Ad-Cx43DN). Infection of LNCaP (but not PC3) cells with Ad-Cx43 greatly increased their sensitivity to killing by tumor necrosis factor α (TNFα), anti-Fas antibodies, and TRAIL as quantified using an MTS assay. The TNFα-induced cell death was dependent on cell density, and it was associated with increased annexin V staining, an increased proportion of sub-G1 cells, and activation of caspase 8. The TNFα-induced effects on Ad-Cx43-infected LNCaP cells were blocked by co-infection with Ad-Cx43DN or by pre-incubation with neutralizing antibodies directed against TNFα receptor 1. These results demonstrate that TNFα induces apoptosis in LNCaP cells by signaling through TNFα receptor 1 and that expression of functional Cx43 gap junction channels increases their sensitivity to TNFα.

Inhibition of Wound TGF Beta-1 by Celecoxib: A Possible Therapeutic Route for Scar Free Wound

“…They have either agonising or antagonising effects on phases of healing, they can be -pro inflammatory or anti-inflammatory, profibrotic or antifibrotic, pro-proliferative or -anti proliferative…etc [41][42][43][44][45][46][47][48]. The Wound healing requires a balance between these endogenously produced mediators [43][44][45][46][47][48] to progress in a coordinated manner without complications [2,33,34]. The basic Collagen bundles arranged in a reticular pattern closely resembling that of the normal dermis resulting in dermis indistinguishable from that the of surrounding unwounded skin.…”

Prognostic value of connexin43 expression in patients with clinically localized prostate cancer

“…Wang et al 3 showed that Cx43 increased the sensitivity of prostate cancer cells to tumour necrosis factor-a-induced apoptosis. Fukushima et al 1 showed that combination therapy of Cx43 and docetaxel was significantly more cytotoxic when cells were treated with docetaxel after 24 h of Cx43 transfection, suggesting that Cx43 affected sensitivity to docetaxel.…”

“…[1][2][3] The channels are bicellular structures formed by the members of a family of about 20 related but distinct Cxs. 4,5 Six Cx monomers assemble to form a hemi-gap junction channel or connexon, which, in turn, forms a complete gap junction channel by docking with connexon from an adjacent cell.…”

“…4,5 Six Cx monomers assemble to form a hemi-gap junction channel or connexon, which, in turn, forms a complete gap junction channel by docking with connexon from an adjacent cell. 2,3 The phosphorylation of connexin43 (Cx43) in its life cycle has been implicated in the regulation of a broad variety of Cx processes, such as the trafficking, assembly/disassembly, degradation, as well as the gating of gap junction channels. In addition, Cx43 phosphorylation is known to have a role in gap junctional plaque formation and activity.…”

Tramadol and Flurbiprofen Depress the Cytotoxicity of Cisplatin via Their Effects on Gap Junctions

“…It has been established that gap junctions increase the sensitivity of prostate cancer cells to tumor necrosis factor-α-induced apoptosis (14). Such a "bystander" effect has also been observed for ionizing radiation, in which cells not irradiated but coupled to irradiated cells become damaged or die (15)(16)(17).…”