Connexin 32 affects doxorubicin resistance in hepatocellular carcinoma cells mediated by Src/FAK signaling pathway

Yu, Man; Zou, Qi; Wu, Xiao-xiang; Han, Guangshu; Tong, Xuhui

doi:10.1016/j.biopha.2017.09.065

Cited by 19 publications

(33 citation statements)

References 36 publications

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“…3) Exerting biological effects as an independent protein. Cx itself plays an important role in physiological and pathological processes such as cell growth, apoptosis, oncogenesis, tumor invasion, and metastasis by regulating intracellular signal transduction and possible downstream gene transcription 42,43. This study provided evidence, for the first time, that Cx32 could partly restore chemosensitivity in OR HCC cells by reversing EMT.…”

Section: Discussionmentioning

confidence: 63%

<p>Connexin 32 downregulation is critical for chemoresistance in oxaliplatin-resistant HCC cells associated with EMT</p>

Yang¹,

Yao²,

Du³

et al. 2019

CMAR

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Background: Oxaliplatin (OXA)-based chemotherapy is critical in the management of advanced hepatocellular carcinoma (HCC); however, acquired drug resistance has largely restricted its clinical efficacy. This study aims to explore the key mechanisms and regulatory factors determining chemosensitivity in HCC. Methods: We developed OXA-resistant (OR) HCC cells and used multiple methods, including real-time RT-PCR, Western blot, immunofluorescence, transwell invasion assay, wound-healing assay, MTT assay, gene transfection, and immunohistochemistry to achieve our goals. Results: We found that OR HCC cells showed a typical epithelial–mesenchymal transition (EMT) phenotype. Meanwhile, the expression of Cx32, a major member of the liver connexin (Cx) family, was lowly expressed in OR HCC cells. Downregulation of Cx32 in parental HCC cells led to EMT induction and thereby reduced OXA cytotoxicity, while Cx32 upregulation in OR HCC cells could reverse the EMT phenotype and partially restore chemosensitivity to OXA. Finally, in human HCC tissue samples, Cx32 was positively correlated with the expression of the EMT marker E-cadherin and negatively correlated with the expression of Vimentin. Conclusion: Our findings demonstrated that downregulation of Cx32 may be an important determinant for HCC cells to acquire EMT-related acquired drug resistance to OXA, and targeting Cx32 could be a novel strategy to overcome OXA resistance in HCC.

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Section: Discussionmentioning

confidence: 63%

<p>Connexin 32 downregulation is critical for chemoresistance in oxaliplatin-resistant HCC cells associated with EMT</p>

Yang¹,

Yao²,

Du³

et al. 2019

CMAR

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“…The same overall trend may be seen in hepatocellular carcinoma (HCC) (Yu et al 2017). In normal liver, Cx43 expression is not detected in parenchymal liver cells (Zhang et al 2007), whereas in liver cancer, Cx43 is present in these cells, and enhances invasion, migration and lung metastasis in rats (Ogawa et al 2012).…”

Section: Role In Liver Diseasementioning

confidence: 75%

“…Studies with Cx32 knock-out rats indicate increased susceptibility to tumor development compared to wild-type counterparts (Hokaiwado et al 2007;Kato et al 2016), while Cx32 10 overexpression was reported to inhibit metastasis and proliferation of HCC cells via p53 and protein kinase B (Akt) pathways (Zhao et al 2015). In addition, Cx32-based gap junctions are crucial to avoid chemotherapy resistance, as these mediate the so-called bystander effect, including passage of anti-tumor agents to neighboring tumor cells (Yu et al 2017;Xiang et al 2019;Hong et al 2012). The same bystander effect was also noted for Cx26 (Yang et al 2016), of which the expression is decreased in HCC through methylation of its gene promotor (Vinken et al 2012).…”

Section: Role In Liver Diseasementioning

confidence: 99%

Targeting gap junctional intercellular communication by hepatocarcinogenic compounds

Leroy

Pieters

Tabernilla

et al. 2020

Journal of Toxicology and Environmental Health, Part B

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Gap junctions in liver, as in other organs, play a critical role in tissue homeostasis. Inherently, these cellular constituents are major targets for systemic toxicity and diseases, including cancer.This review provides an overview of chemicals that compromise liver gap junctions, in particular biological toxins, organic solvents, pesticides, pharmaceuticals, peroxides, metals and phthalates. The focus in this review is placed upon the mechanistic scenarios that underlie these adverse effects. Further, the potential use of gap junctional activity as an in vitro biomarker to identify non-genotoxic hepatocarcinogenic chemicals is discussed.

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“…Combining Dasatinib with Dox has been shown to synergistically inhibit growth as well as migration and invasion of MDA-MB-231 cells [73] and had a synergistic anti-proliferative effect in a highly tumorigenic ovarian cancer cell line that had high Src levels [74]. In a Doxresistant sarcoma cell line, combination treatment of Dox with Dasatinib was shown to decrease cell viability [75], and Dasatinib increased therapeutic efficacy of Dox in Dox-resistant hepatocellular carcinoma cells [76]. However, all these studies probed the efficacy of combination treatment in highly aggressive cells utilizing lethal doses of Dox treatment.…”

Section: Discussionmentioning

confidence: 99%

Sublethal doxorubicin promotes migration and invasion of breast cancer cells: role of Src Family non-receptor tyrosine kinases

et al. 2021

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Background Doxorubicin (Dox) is a widely used chemotherapy, but its effectiveness is limited by dose-dependent side effects. Although lower Dox doses reduce this risk, studies have reported higher recurrence of local disease with no improvement in survival rate in patients receiving low doses of Dox. To effectively mitigate this, a better understanding of the adverse effects of suboptimal Dox doses is needed. Methods Effects of sublethal dose of Dox on phenotypic changes were assessed with light and confocal microscopy. Migratory and invasive behavior were assessed by wound healing and transwell migration assays. MTT and LDH release assays were used to analyze cell growth and cytotoxicity. Flow cytometry was employed to detect cell surface markers of cancer stem cell population. Expression and activity of matrix metalloproteinases were probed with qRT-PCR and zymogen assay. To identify pathways affected by sublethal dose of Dox, exploratory RNAseq was performed and results were verified by qRT-PCR in multiple cell lines (MCF7, ZR75-1 and U-2OS). Regulation of Src Family kinases (SFK) by key players in DNA damage response was assessed by siRNA knockdown along with western blot and qRT-PCR. Dasatinib and siRNA for Fyn and Yes was employed to inhibit SFKs and verify their role in increased migration and invasion in MCF7 cells treated with sublethal doses of Dox. Results The results show that sublethal Dox treatment leads to increased migration and invasion in otherwise non-invasive MCF7 breast cancer cells. Mechanistically, these effects were independent of the epithelial mesenchymal transition, were not due to increased cancer stem cell population, and were not observed with other chemotherapies. Instead, sublethal Dox induces expression of multiple SFK—including Fyn, Yes, and Src—partly in a p53 and ATR-dependent manner. These effects were validated in multiple cell lines. Functionally, inhibiting SFKs with Dasatinib and specific downregulation of Fyn suppressed Dox-induced migration and invasion of MCF7 cells. Conclusions Overall, this study demonstrates that sublethal doses of Dox activate a pro-invasive, pro-migration program in cancer cells. Furthermore, by identifying SFKs as key mediators of these effects, our results define a potential therapeutic strategy to mitigate local invasion through co-treatment with Dasatinib.

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Connexin 32 affects doxorubicin resistance in hepatocellular carcinoma cells mediated by Src/FAK signaling pathway

Cited by 19 publications

References 36 publications

<p>Connexin 32 downregulation is critical for chemoresistance in oxaliplatin-resistant HCC cells associated with EMT</p>

<p>Connexin 32 downregulation is critical for chemoresistance in oxaliplatin-resistant HCC cells associated with EMT</p>

Targeting gap junctional intercellular communication by hepatocarcinogenic compounds

Sublethal doxorubicin promotes migration and invasion of breast cancer cells: role of Src Family non-receptor tyrosine kinases

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