Modulation of the HSV-TK/ganciclovir bystander effect by n-butyrate in glioblastoma: Correlation with gap-junction intercellular communication

The radiation-induced bystander effect (RIBE) can increase cellular toxicity in a gap junction dependent manner in unirradiated bystander cells. Recent reports have suggested that cisplatin toxicity can also be mediated by functional gap junction intercellular communication (GJIC). In this study using lung and ovarian cancer cell lines, we showed that cisplatin cytotoxicity is mediated by cellular density. This effect is ablated when GJA1 or Connexin 43 (Cx43) is targeted, a gap junction gene and protein, respectively, leading to cisplatin resistance but only at high or gap junction forming density. We also observed that the cisplatin-mediated bystander effect was elicited as DNA Double Strand Breaks (DSBs) with positive H2AX Ser139 phosphorylation (γH2AX) formation, an indicator of DNA DSBs. These DSBs are not observed when gap junction formation is prevented. We next showed that cisplatin is not the “death” signal traversing the gap junctions by utilizing the cisplatin-GG intrastrand adduct specific antibody. Finally, we also showed that cells deficient in the structure-specific DNA endonuclease ERCC1-ERCC4 (ERCC1-XPF), an important mediator of cisplatin resistance, further sensitized when treated with cisplatin in the presence of gap junction forming density. Taken together, these results demonstrate the positive effect of GJIC on increasing cisplatin cytotoxicity.

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Hypoxia and Proton microbeam: Role of Gap Junction Intercellular Communication in Inducing Bystander Responses on Human Lung Cancer Cells and Normal Cells

Radiation Research ◽

10.1667/rade-21-00112.1 ◽

2022 ◽

Author(s):

Narongchai Autsavapromporn ◽

Alisa Kobayashi ◽

Cuihua Liu ◽

Churdsak Jaikang ◽

Tengku Ahbrizal Tengku Ahmad ◽

...

Keyword(s):

Gap Junction ◽

Cancer Cells ◽

Intercellular Communication ◽

Bystander Effect ◽

A549 Cells ◽

Human Lung Cancer ◽

Tumor Resistance ◽

Normal Cells ◽

Gap Junction Intercellular Communication ◽

High Let

Radiation-induced bystander effect (RIBE) has been identified as an important contributing factor to tumor resistance and normal tissue damage. However, the RIBE in cancer and normal cells under hypoxia remain unclear. In this study, confluent A549 cancer and WI-38 normal cells were subjected to condition of hypoxia or normoxia, before exposure to high-LET protons microbeam. After 6 h incubation, cells were harvested and assayed for colony formation, micronucleus formation, chromosome aberration and western blotting. Our results show that there were differences of RIBE in bystander A549 and WI-38 cells under hypoxia and normoxia. The differences were also observed in the roles of HIF-1α expression in bystander A549 and WI-38 cells under both conditions. Furthermore, inhibition of gap junction intercellular communication (GJIC) showed a decrease in toxicity of hypoxia-treated bystander A549 cells, but increased in bystander WI-38 cells. These findings clearly support that GJIC protection of bystander normal cells from toxicity while enhancing in bystander cancer cells. Together, the data show a promising strategy for high-LET radiation in designing an entire new line of drugs, either increase or restore GJIC in bystander cancer cells which in turn leads to enhancement of radiation accuracy for treatment of hypoxic tumors.

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Extract from the Zooxanthellate Jellyfish Cotylorhiza tuberculata Modulates Gap Junction Intercellular Communication in Human Cell Cultures

Marine Drugs ◽

10.3390/md11051728 ◽

2013 ◽

Vol 11 (5) ◽

pp. 1728-1762 ◽

Cited By ~ 32

Author(s):

Antonella Leone ◽

Raffaella Lecci ◽

Miriana Durante ◽

Stefano Piraino

Keyword(s):

Gap Junction ◽

Cell Cultures ◽

Human Cell ◽

Intercellular Communication ◽

Gap Junction Intercellular Communication ◽

Human Cell Cultures

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Connexin expression by alveolar epithelial cells is regulated by extracellular matrix

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.2.l191 ◽

2001 ◽

Vol 280 (2) ◽

pp. L191-L202 ◽

Cited By ~ 32

Author(s):

Yihe Guo ◽

Cara Martinez-Williams ◽

Clare E. Yellowley ◽

Henry J. Donahue ◽

D. Eugene Rannels

Keyword(s):

Extracellular Matrix ◽

Epithelial Cells ◽

Gap Junction ◽

Intercellular Communication ◽

Translational Regulation ◽

Alveolar Epithelial Cells ◽

Alveolar Type ◽

Type Ii ◽

Gap Junction Intercellular Communication ◽

Type Ii Cell

Extracellular matrix (ECM) proteins promote attachment, spreading, and differentiation of cultured alveolar type II epithelial cells. The present studies address the hypothesis that the ECM also regulates expression and function of gap junction proteins, connexins, in this cell population. Expression of cellular fibronectin and connexin (Cx) 43 increase in parallel during early type II cell culture as Cx26 expression declines. Gap junction intercellular communication is established over the same interval. Cells plated on a preformed, type II cell-derived, fibronectin-rich ECM demonstrate accelerated formation of gap junction plaques and elevated gap junction intercellular communication. These effects are blocked by antibodies against fibronectin, which cause redistribution of Cx43 protein from the plasma membrane to the cytoplasm. Conversely, cells cultured on a laminin-rich ECM, Matrigel, express low levels of Cx43 but high levels of Cx26, reflecting both transcriptional and translational regulation. Cx26 and Cx43 thus demonstrate reciprocal regulation by ECM constituents.

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