Gap junctions propagate opposite effects in normal and tumor testicular cells in response to cisplatin

Hong, Xin; Wang, Qin; Yang, Yan; Zheng, Su-ping; Tong, Xuhui; Zhang, Suzhi; Tao, Liang; Harris, Andrew L.

doi:10.1016/j.canlet.2011.11.019

Cited by 53 publications

(60 citation statements)

References 51 publications

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“…The assay for GJ function was performed as described by Hong et al (20) and Tong et al (21). Donor cells and receiver cells were grown to confluence in 12-well plates.…”

Section: Modulation Of Gjicmentioning

confidence: 99%

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

Jiang

Dong

et al. 2016

Oncology Letters

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Abstract. Gap junctions (GJs) serve the principal role in the antineoplastic (cytotoxicity and induced apoptosis) effect of chemical drugs. The aim of the present study was to determine the effect of GJ intercellular communication (GJIC) composed of connexin 43 (Cx43) on adriamycin cytotoxicity in breast cancer cells. Four cell lines (Hs578T, MCF-7, MDA-MB-231 and SK-BR-3) with different degree of malignancy were used in the study. The results of western blotting and immunofluorescence revealed that, in Hs578T and MCF-7 cells, which have a low degree of malignancy, the expression levels of Cx43 and GJIC were higher than those in MDA-MB-231 and SK-BR-3 cells (which have a high degree of malignancy). In Hs578T and MCF-7 cells, where GJ could be formed, the function of GJ was modulated by a pharmacological potentiators [retinoid acid (RA)]/inhibitors [oleamide and 18-α-glycyrrhetinic acid (18-α-GA)] and small interfering RNA (siRNA). In high-density cells (where GJ was formed), enhancement of GJ function by RA increased the cytotoxicity of adriamycin, while inhibition of GJ function by oleamide/18-α-GA and siRNA decreased the cytotoxicity caused by adriamycin. Notably, the modulation of GJ did not affect the survival of cells treated with adriamycin when cells were in low density (no GJ was formed). The present study illustrated the association between GJIC and the antitumor effect of adriamycin in breast cancer cells. The cytotoxicity of adriamycin on breast cancer cells was increased when the function of gap junctions was enhanced.

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“…The assay for GJ function was performed as described by Hong et al (20) and Tong et al (21). Donor cells and receiver cells were grown to confluence in 12-well plates.…”

Section: Modulation Of Gjicmentioning

confidence: 99%

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

Jiang

Dong

et al. 2016

Oncology Letters

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“…However, Cx43 enhances paclitaxel cytotoxicity in HeLa cells (28) and cisplatin cytotoxicity in mesothelioma cells (29). The mechanism of the effect of Cx43 on antitumor drugs is complex; a previous study reported that Cx43 sensitized tumor testicular cells in response to cisplatin but caused normal testicular cells to become resistant to cisplatin (20). Therefore, three CRC cell lines, LoVo, HCT106 and HCT116, were used in the present study in order to perform a comprehensive analysis of the role of Cx43 in CRC, and it was demonstrated that Cx43 enhanced paclitaxel cytotoxicity in all three of these cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…2). High culture density ensures GJC function (20), and all transfected cell lines with high culture density were significantly more sensitive to paclitaxel compared with their WT counterparts when they were treated with 20 or 80 nM paclitaxel (P<0.05). At lower concentrations of paclitaxel treatment (1 or 5 nM), the cell viability rates of HCT106 and HCT116 were also significantly decreased by transfection with Cx43 (P<0.05 vs. WT).…”

Section: Cx43 Enhances Paclitaxel-induced Apoptosismentioning

confidence: 97%

Connexin 43 enhances paclitaxel cytotoxicity in colorectal cancer cell lines

Wang¹,

Zhao²,

Zhang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Colorectal cancer has a relatively low sensitivity to paclitaxel. The purpose of this study was to investigate the role of connexin 43 (Cx43), which is a structural component of gap junctional communication (GJC), in paclitaxel cytotoxicity in colorectal cancer cells. Three colorectal cancer cell lines (HCT106, HCT116 and LoVo) were transfected with Cx43 and used to examine paclitaxel cytotoxicity. A western blot assay was used to confirm Cx43 expression in transfected cell lines as well as the expression of several proteins that are associated with paclitaxel cytotoxicity. A parachute dye-coupling assay was used to measure GJC function. An MTT assay was used to analyze the viability of paclitaxel-treated cells. Cx43 expression level and GJC function were significantly upregulated by the transfection (P<0.05). The viability of transfected cells was significantly inhibited compared with that of untransfected cells when treated with paclitaxel (20 or 80 nM) at high culture density but not at low culture density (P<0.05). Cx43 transfection significantly increased the mitotic arrest, tubulin polymerization and apoptosis effects of paclitaxel (P<0.05). It was also found that paclitaxel had an inhibitory effect on GJC function after 12 h of treatment in LoVo cells (P<0.05). These results indicate that Cx43 may serve as a target of paclitaxel chemotherapy for colorectal cancer.

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“…The GJ is the main channel of death signals transferred between the neighboring cells. Death signals not only attack the neighboring cells directly, but also activate various signal pathways, resulting indirectly in cytotoxicity or apoptosis (11,25). In summary, the effects of chemotherapy drugs are amplified by the transfer of death signals between the neighboring cells through the GJ, which is called the 'bystander effect' (26,27).…”

Section: Discussionmentioning

confidence: 99%

Deficiency of gap junction composed of connexin43 contributes to oxaliplatin resistance in colon cancer cells

Zhang

2017

Oncology Letters

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Abstract. Although comprehensive strategies in the treatment of colorectal cancer have been developed for a number of years, the five-year survival rate of metastatic colon cancer remains less than 10%. Oxaliplatin, a commonly used chemotherapeutic agent for metastatic colon cancer, improves the response rate of patients and prolongs patients' progression-free survival. However, the generation of resistance limits the clinical application of oxaliplatin, and the mechanisms of this remain unclear. The present study mainly investigated the effect of the gap junction (GJ) composed of connexin43 (Cx43) on oxaliplatin cytotoxicity in colon cancer cells. Three different methods with distinct mechanisms were used to change the function of Cx43 GJs, including cell culture at different densities, pretreatment with a specific inhibitor or enhancer, and special gene knockdown, to observe the cytotoxicity of oxaliplatin and the level of reactive oxygen species (ROS) mediated by Cx43 GJs. The results revealed that the cytotoxicity of oxaliplatin and the level of ROS were decreased with the downregulation of Cx43 GJ function, but exacerbated with the upregulation of Cx43 GJ function. Moreover, ROS scavenging with N-acetyl-L-cysteine and apocynin decreased the cytotoxicity of oxaliplatin. We concluded that the loss of GJ composed of Cx43 contributed to the resistance of oxaliplatin in colon cancer cells, and the mechanism was associated with intracellular ROS alternation. IntroductionColorectal cancer (CRC) is considered to be one of the most frequent causes of cancer-related morbidity and mortality worldwide (1,2). Although comprehensive strategies in the treatment of CRC have been developed for a number of years, the five-year survival rate of metastatic colon cancer is only 10% (3). In the clinical treatment of metastatic colon cancer, oxaliplatin is commonly used as an essential chemotherapeutic agent, and not only improves the response rate of patients, but also prolongs patients' progression-free survival. Nevertheless, more than 40% of patients still develop significant resistance (3,4). Therefore, how to overcome resistance to oxaliplatin is a key scientific problem to be solved in the treatment of metastatic colon cancers.Connexins are integral membrane proteins, six of which make up a hemi-channel. Two hemi-channels in neighboring cells dock together to form an integral gap junction (GJ). The GJ enables cells to exchange ions and small molecules (with a molecule weight less than 1 kDa) directly, including calcium, glutathione, cyclic adenosine monophosphate and cyclic guanosine monophosphate. Molecules transferred through the GJ are essential for numerous physiological and pathological events (5,6). The connexin gene family constitutes 21 isoforms, the most significant of which is Cx43 (6). The loss of Cx43 is extremely common in the development of cancers and is even involved in advanced stages of tumor progression. The deficiency of Cx43 also contributes to the resistance of chemotherapeutic agents (7). It has been...

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Gap junctions propagate opposite effects in normal and tumor testicular cells in response to cisplatin

Cited by 53 publications

References 51 publications

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

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

Connexin 43 enhances paclitaxel cytotoxicity in colorectal cancer cell lines

Deficiency of gap junction composed of connexin43 contributes to oxaliplatin resistance in colon cancer cells

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