Connexin 43 SUMOylation improves gap junction functions between liver cancer stem cells and enhances their sensitivity to HSVtk/GCV

Shen, Yimeng; Li, Yanxia; Ma, Xiaofang; Wan, Qiaohao; Jiang, Zhongmin; Liu, Yixin; Zhang, Dianying; Liu, Xiaozhi; Wu, Wenhan

doi:10.3892/ijo.2018.4263

Cited by 19 publications

(16 citation statements)

References 31 publications

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“…A recent work has found that the expression levels of Cx43 and Cx46 were increased and reduced, respectively, during GSC differentiation and that targeting of Cx46 compromises GSC maintenance [56]. While Cx43 is almost absent in liver CSCs [57], the accumulation of cytoplasmic Cx32 has been associated with metastasis and enhanced self-renewal of CSCs in human HuH7 hepatoma cells [58]. Some subtypes of breast cancer cells positive for the putative CSC marker CD44 express Cx43 [59, 60].…”

Section: Complex Roles Of Connexins In Cancermentioning

confidence: 99%

“…refs. [114–117]), including a recent one in breast cancer [118] and liver cancer, in which the co-expression of Cx43 and SUMO1 in liver CSCs increased GJIC and their sensitivity to HSV-TK/GCV therapy in vitro and in vivo [57]. However, other studies reported no evidence for a GJIC-mediated bystander effect [119].…”

Section: Targeting Of Connexins In Cancer: Therapeutic Opportunities mentioning

confidence: 99%

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Connexins in cancer: bridging the gap to the clinic

et al. 2019

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Gap junctions comprise arrays of intercellular channels formed by connexin proteins and provide for the direct communication between adjacent cells. This type of intercellular communication permits the coordination of cellular activities and plays key roles in the control of cell growth and differentiation and in the maintenance of tissue homoeostasis. After more than 50 years, deciphering the links among connexins, gap junctions and cancer, researchers are now beginning to translate this knowledge to the clinic. The emergence of new strategies for connexin targeting, combined with an improved understanding of the molecular bases underlying the dysregulation of connexins during cancer development, offers novel opportunities for clinical applications. However, different connexin isoforms have diverse channel-dependent and-independent functions that are tissue and stage specific. This can elicit both pro-and anti-tumorigenic effects that engender significant challenges in the path towards personalised medicine. Here, we review the current understanding of the role of connexins and gap junctions in cancer, with particular focus on the recent progress made in determining their prognostic and therapeutic potential.

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Section: Complex Roles Of Connexins In Cancermentioning

confidence: 99%

Section: Targeting Of Connexins In Cancer: Therapeutic Opportunities mentioning

confidence: 99%

Connexins in cancer: bridging the gap to the clinic

et al. 2019

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“…A previous study indicated that Connexin 43 (Cx43), which is a protein involved in gap junctional intercellular communication, can be covalently modified and regulated by SUMO1 in liver cancer stem cells ( 57 ). In addition, Cx43 SUMOylation can improve gap junction functions and enhance cell sensitivity to HSVtk/GCV ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of SENP1 reduces the stemness capacity of osteosarcoma stem cells and increases their sensitivity to HSVtk/GCV

Liu

et al. 2018

Int J Oncol

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Osteosarcoma stem cells are able to escape treatment with conventional chemotherapeutic drugs, as the majority of them are in a quiescent state. Recent reports have suggested that small ubiquitin-like modifiers (SUMOs) serve important roles in the maintenance of cancer stem cell stemness. Therefore, a potential strategy to increase the effectiveness of chemotherapeutic agents is to interfere with SUMO modification of proteins associated with the maintenance of stemness in osteosarcoma stem cells. The present study revealed a significant decrease in the expression of SUMO1 specific peptidase 1 (SENP1) in osteosarcoma tissues and osteosarcoma cell lines, and SENP1 expression was much lower in osteosarcoma stem cells than in non-cancer stem cells. Further experiments indicated that the low levels of SENP1 were essential for maintenance of stemness in osteosarcoma stem cells. Overexpression of SENP1 resulted in a marked decrease in the maintenance of stemness, but only slightly induced apoptosis of osteosarcoma cells, which is crucial to reduce the side effects of drugs on normal precursor cells. Finally, SENP1 overexpression led to a significant increase in the sensitivity of osteosarcoma stem cells to the herpes simplex virus 1 thymidine kinase gene in combination with ganciclovir in vitro and in vivo. In conclusion, the present study described a novel method to increase the sensitivity of osteosarcoma stem cells to chemotherapeutic drugs. Notably, this approach may significantly reduce the required dose of conventional chemotherapeutic drugs and reduce side effects.

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“…At the level of CSCs, many studies have found that some properties of CSCs, such as self-renewal, depend on GJIC in breast and hepatic cancers [108,109]. In addition, it has been found that GIJC was an integral part of CSC function also resulting in tumor progression [110,111]. Hitomi and colleagues demonstrated that GJs are present in glioblastoma CSCs and that Cx46 is essential for CSC proliferation, self-renewal, and tumor initiation in vivo, whereas Cx43 is expressed by non-CSCs [110].…”

Section: Gjic and Hallmarks Of Cancermentioning

confidence: 99%

Gap Junction Intercellular Communication in the Carcinogenesis Hallmarks: Is This a Phenomenon or Epiphenomenon?

Zefferino

Piccoli

Gioia

et al. 2019

Cells

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If occupational tumors are excluded, cancer causes are largely unknown. Therefore, it appeared useful to work out a theory explaining the complexity of this disease. More than fifty years ago the first demonstration that cells communicate with each other by exchanging ions or small molecules through the participation of connexins (Cxs) forming Gap Junctions (GJs) occurred. Then the involvement of GJ Intercellular Communication (GJIC) in numerous physiological cellular functions, especially in proliferation control, was proven and accounts for the growing attention elicited in the field of carcinogenesis. The aim of the present paper is to verify and discuss the role of Cxs, GJs, and GJIC in cancer hallmarks, pointing on the different involved mechanisms in the context of the multi-step theory of carcinogenesis. Functional GJIC acts both as a tumor suppressor and as a tumor enhancer in the metastatic stage. On the contrary, lost or non-functional GJs allow the uncontrolled proliferation of stem/progenitor initiated cells. Thus, GJIC plays a key role in many biological phenomena or epiphenomena related to cancer. Depending on this complexity, GJIC can be considered a tumor suppressor in controlling cell proliferation or a cancer ally, with possible preventive or therapeutic implications in both cases.

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Connexin 43 SUMOylation improves gap junction functions between liver cancer stem cells and enhances their sensitivity to HSVtk/GCV

Cited by 19 publications

References 31 publications

Connexins in cancer: bridging the gap to the clinic

Connexins in cancer: bridging the gap to the clinic

Overexpression of SENP1 reduces the stemness capacity of osteosarcoma stem cells and increases their sensitivity to HSVtk/GCV

Gap Junction Intercellular Communication in the Carcinogenesis Hallmarks: Is This a Phenomenon or Epiphenomenon?

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