Influence of gap junction intercellular communication composed of connexin 43 on the antineoplastic effect of adriamycin in breast cancer cells

Jiang, Guojun; Dong, Shuying; Yu, Man; Han, Xiao‐Jian; Zheng, Chao; Zhu, Xiaodong; Tong, Xuhui

doi:10.3892/ol.2016.5471

Cited by 17 publications

(12 citation statements)

References 56 publications

(66 reference statements)

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“…Arguably, this gap junction hyperactivity (above baseline level) may signify some form of abnormality [64] or pathology. However, in a recent report by Jiang et al, it was demonstrated that high levels of Cx43-mediated gap junctional communication attenuate the degree of malignancy in multiple cancer cell lines [65]. Considering that cancer and vascular diseases share common pathology progression pathways [66], the results of the study conducted by Jiang et al can be extrapolated to suggest that over-recovery of interendothelial gap junction-mediated dye spread is not necessarily pathological and may actually be physiological beneficial.…”

Section: Discussionmentioning

confidence: 99%

Regeneration of glycocalyx by heparan sulfate and sphingosine 1-phosphate restores inter-endothelial communication

et al. 2017

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Vasculoprotective endothelium glycocalyx (GCX) shedding plays a critical role in vascular disease. Previous work demonstrated that GCX degradation disrupts endothelial cell (EC) gap junction connexin (Cx) proteins, likely blocking interendothelial molecular transport that maintains EC and vascular tissue homeostasis to resist disease. Here, we focused on GCX regeneration and tested the hypothesis that vasculoprotective EC function can be stimulated via replacement of GCX when it is shed. We used EC with [i] intact heparan sulfate (HS), the most abundant GCX component; [ii] degraded HS; or [iii] HS that was restored after enzyme degradation, by cellular self-recovery or artificially. Artificial HS restoration was achieved via treatment with exogenous HS, with or without the GCX regenerator and protector sphingosine 1- phosphate (S1P). In these cells we immunocytochemically examined expression of Cx isotype 43 (Cx43) at EC borders and characterized Cx-containing gap junction activity by measuring interendothelial spread of gap junction permeable Lucifer Yellow dye. With intact HS, 60% of EC borders expressed Cx43 and dye spread to 2.88 ± 0.09 neighboring cells. HS degradation decreased Cx43 expression to 30% and reduced dye spread to 1.87± 0.06 cells. Cellular self-recovery of HS restored baseline levels of Cx43 and dye transfer. Artificial HS recovery with exogenous HS partially restored Cx43 expression to 46% and yielded dye spread to only 1.03 ± 0.07 cells. Treatment with both HS and S1P, recovered HS and restored Cx43 to 56% with significant dye transfer to 3.96 ± 0.23 cells. This is the first evidence of GCX regeneration in a manner that effectively restores vasculoprotective EC communication.

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Section: Discussionmentioning

confidence: 99%

Regeneration of glycocalyx by heparan sulfate and sphingosine 1-phosphate restores inter-endothelial communication

et al. 2017

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“…Previous evidence suggests that Cx43 expression levels are negatively correlated with HER2 expression [ 21 , 22 ]. Additional experimental evidence indicates that HER2+ breast cancer cell lines have reduced Cx43 expression as compared to ER+ breast cancer cells [ 23 , 24 ]. Somewhat paradoxically, the analysis presented here, suggests that high Cx43 expression levels correlates with reduced relapse free survival (RFS) in HER2-positive (HER2+) breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated connexin 43 in HER2-positive drug resistant breast cancer cells enhances proliferation and migration

et al. 2017

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Connexin 43 (Cx43) is a gap junction protein whose function in the development of breast cancer and in breast cancer progression remains unclear. Evidence suggests that Cx43 (GJA1) mRNA and protein expression is altered in breast tumors. However, reports indicate both increased and decreased Cx43 levels in human breast cancer samples. Studies also suggest that loss of Cx43 regulated gap junction intercellular communication is a common feature of breast malignancies that potentially correlates with histological stage. Further evidence suggests that Cx43 (GJA1) mRNA expression is negatively correlated with HER2 positivity but a relationship between Cx43 and HER2 in breast cancer is not well defined. Therefore, in this study, we sought to evaluate the relationship between Cx43 activity, HER2, and drug resistance. Using HER2+ breast cancer cell lines that are sensitive or resistant to HER2 inhibitor, we evaluated Cx43 gap junction function. We found that Cx43 gap junction activity is completely lost in drug resistant HER2-positive (HER2+) breast cancer cells, whereas Cx43 gap junction activity can be restored by Cx43 overexpression in drug sensitive HER2+ cells. Moreover, the dysregulation of Cx43 resulted in increased tumorigenic and migratory capacity of the HER2+ drug resistant breast cancer cells.

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“…To determine whether the dye communication between PVMs GFP and ECs involved Cx43 GJ protein, we employed a GJ blocker, 18α-GA, which has been reported to block Cx43 mediated intercellular communication (Zhu et al, 2016;Jiang et al, 2017). As shown in Figures 2C,D, we found that blocking GJ with 18α-GA significantly blocked dye transfer from an injected PVM GFP to the connected ECs.…”

Section: Cx43 Mediation Of Pvm-ec Communication Tested In An In Vitromentioning

confidence: 86%

“…Since the Alexa dye is negatively charged, a negative potential (−10 mV) was applied to expedite diffusion of the dye. To block the GJ, 18α-Glycyrrhetinic acid (18α-GA,10 μM, G8503, Sigma-Aldrich, St. Louis, MO) was added to the culture medium for 30 min (Zhu et al, 2016;Jiang et al, 2017).…”

Section: Dye Injection With a Patch-clamp Pipettementioning

confidence: 99%

Suppression of Connexin 43 Leads to Strial Vascular Hyper-Permeability, Decrease in Endocochlear Potential, and Mild Hearing Loss

et al. 2020

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Objective: Connexin 43 (Cx43) is a protein constituent of gap junctions (GJs) in various barrier cells, especially astrocytes and microglia of the blood-brain-barrier (BBB), where it plays an important role in intercellular communication and regulation of the barrier. Despite the importance of Cx43 in other blood barriers, not much attention has been paid to expression and function of Cx43 in the blood-labyrinth-barrier (BLB) of the stria vascularis in the cochlea. Methods: We used multiple research approaches, including immunocytochemical staining, patch-clamp dye loading technique, real-time quantitative reverse transcription (RT)-PCR, western blot, measurement of endocochlear potential (EP) with an electrode through the scala media, and auditory brainstem response to test hearing function. Results: We found Cx43 expressed in vascular endothelial cells (ECs) and perivascular resident macrophages (PVMs) in the stria vascularis of adult C57BL/6 mouse cochleae. In particular, we found Cx43 expressed in foot processes of PVMs at points of contact with the endothelium. Consistent with Cx43 expression in vivo, we also found Cx43 expressed in EC-EC and EC-PVM interfaces in a co-cultured cell line model. Using a patch-clamp dye loading technique, we demonstrated that Alexa Fluor ® 568 dye injected into PVMs diffuses to connected neighboring ECs. The functional coupling between the ECs and PVMs is blocked by 18α-Glycyrrhetinic acid (18α-GA), a GJ blocker. Suppression of Cx43 with small interfering RNA (siRNA) in vivo significantly elevated hearing threshold and caused the EP to drop and the blood barrier to become more permeable. In further study, using in vitro primary EC cell line models, we demonstrated that suppression of Cx43 disrupts intercellular tight junctions (TJs) in the EC monolayer and increases endothelial monolayer permeability. Conculsion: Taken together, these findings underscore the importance of Cx43 expression in the normal ear for maintaining BLB integrity, normal EP, and hearing function.

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Influence of gap junction intercellular communication composed of connexin 43 on the antineoplastic effect of adriamycin in breast cancer cells

Cited by 17 publications

References 56 publications

Regeneration of glycocalyx by heparan sulfate and sphingosine 1-phosphate restores inter-endothelial communication

Regeneration of glycocalyx by heparan sulfate and sphingosine 1-phosphate restores inter-endothelial communication

Dysregulated connexin 43 in HER2-positive drug resistant breast cancer cells enhances proliferation and migration

Suppression of Connexin 43 Leads to Strial Vascular Hyper-Permeability, Decrease in Endocochlear Potential, and Mild Hearing Loss

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