Connexins—Therapeutic Targets in Cancers

Nalewajska, Magdalena; Marchelek-Myśliwiec, Małgorzata; Opara-Bajerowicz, Martyna; Dziedziejko, Violetta; Pawlik, Andrzej

doi:10.3390/ijms21239119

Cited by 20 publications

(16 citation statements)

References 163 publications

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“…However, this scientific area is quite poorly studied and further, we focus on the direct or indirect involvement of cholesterol precursors in cancers. We found that cholesterol precursors can be formally divided into three groups ( Table 4 ) depending on their impact on carcinogenesis [ 50 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 ].…”

Section: Discussionmentioning

confidence: 99%

Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context

et al. 2021

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A global protein interactome ensures the maintenance of regulatory, signaling and structural processes in cells, but at the same time, aberrations in the repertoire of protein–protein interactions usually cause a disease onset. Many metabolic enzymes catalyze multistage transformation of cholesterol precursors in the cholesterol biosynthesis pathway. Cancer-associated deregulation of these enzymes through various molecular mechanisms results in pathological cholesterol accumulation (its precursors) which can be disease risk factors. This work is aimed at systematization and bioinformatic analysis of the available interactomics data on seventeen enzymes in the cholesterol pathway, encoded by HMGCR, MVK, PMVK, MVD, FDPS, FDFT1, SQLE, LSS, DHCR24, CYP51A1, TM7SF2, MSMO1, NSDHL, HSD17B7, EBP, SC5D, DHCR7 genes. The spectrum of 165 unique and 21 common protein partners that physically interact with target enzymes was selected from several interatomic resources. Among them there were 47 modifying proteins from different protein kinases/phosphatases and ubiquitin-protein ligases/deubiquitinases families. A literature search, enrichment and gene co-expression analysis showed that about a quarter of the identified protein partners was associated with cancer hallmarks and over-represented in cancer pathways. Our results allow to update the current fundamental view on protein–protein interactions and regulatory aspects of the cholesterol synthesis enzymes and annotate of their sub-interactomes in term of possible involvement in cancers that will contribute to prioritization of protein targets for future drug development.

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Section: Discussionmentioning

confidence: 99%

Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context

et al. 2021

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“…The functional modulation of GJs, inhibition as well as enhancement, has been proposed as a novel strategy for the treatment of various diseases. These include cardiac diseases, such as arrhythmias, remodeling after cardiac infarction, and atherosclerosis [ 33 , 34 ], brain diseases, e.g., epilepsy and neurodegenerative diseases [ 35 , 36 ], and even cancer [ 37 ]. Notably, a recent study suggested that loss of GJ coupling represents a cause of human temporal lobe epilepsy [ 38 ].To identify novel GJ modulators, a suitable assay for compound screening was required.…”

Section: Discussionmentioning

confidence: 99%

A Cellular Assay for the Identification and Characterization of Connexin Gap Junction Modulators

Danish

Gedschold

Hinz

et al. 2021

IJMS

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Connexin gap junctions (Cx GJs) enable the passage of small molecules and ions between cells and are therefore important for cell-to-cell communication. Their dysfunction is associated with diseases, and small molecules acting as modulators of GJs may therefore be useful as therapeutic drugs. To identify GJ modulators, suitable assays are needed that allow compound screening. In the present study, we established a novel assay utilizing HeLa cells recombinantly expressing Cx43. Donor cells additionally expressing the Gs protein-coupled adenosine A2A receptor, and biosensor cells expressing a cAMP-sensitive GloSensor luciferase were established. Adenosine A2A receptor activation in the donor cells using a selective agonist results in intracellular cAMP production. The negatively charged cAMP migrates via the Cx43 gap junctions to the biosensor cells and can there be measured by the cAMP-dependent luminescence signal. Cx43 GJ modulators can be expected to impact the transfer of cAMP from the donor to the biosensor cells, since cAMP transit is only possible via GJs. The new assay was validated by testing the standard GJ inhibitor carbenoxolon, which showed a concentration-dependent inhibition of the signal and an IC50 value that was consistent with previously reported values. The assay was demonstrated to be suitable for high-throughput screening.

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“…Cxs are transmembrane proteins, which are responsible for intercellular communication ( 38 ). Cx43, a member of the Cx family, has been identified as the main component of the gap junction channels in astrocytes.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑206 relieves irradiation‑induced neuroinflammation by regulating connexin 43

Zeng

2021

Exp Ther Med

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Radiation therapy has been widely used for the treatment of various types of cancer; however, it may cause neuroinflammation during the pathological process of the disease. Astrocytes, the most abundant cell type in the central nervous system, have been confirmed to play vital roles in various diseases. Connexin (Cx)43, the main Cx type in astrocytes, which has been identified as a direct target gene of microRNA (miR)-206, was found to be involved in diseases pathologies in regions with astrocytes. The aim of the present study was to investigate the mechanism through which γ-radiation may cause astrocyte neuroinflammation and determine the specific mechanism underlying the effects of miR-206 in irradiation-induced HA-1800 cells. A dual-luciferase reporter system was used to predict and verify the target binding site between Cx43 and miR-206. HA-1800 cell viability and apoptosis were determined using a MTT assay and flow cytometry, respectively. In addition, the HA-1800 cells were induced by γ-radiation, then the protein and mRNA expression levels of Cx43, miR-206 and cleaved-caspase-3 were determined using western blot and reverse transcription-quantitative PCR analyses, respectively. ELISA was also performed to evaluate the concentrations of different inflammatory cytokines (TNF-α, IL-β, IL-6 and IFN-γ). The dual-luciferase reporter system indicated that Cx43 was a direct target of miR-206. miR-206 mimics increased the expression level of miR-206 in the astrocytes. Irradiation suppressed cell proliferation, increased apoptotic cells and enhanced cleaved-caspase-3 expression and inflammatory cytokines secretion in astrocytes. Furthermore, miR-206 was found to be downregulated and its expression was inversely associated with that of Cx43 in γ-radiation-induced astrocytes.Overexpression of miR-206 enhanced miR-206 and suppressed Cx43 expression, while Cx43 was upregulated in HA-1800 cells transfected with miR-206 mimic + Cx43-plasmid. However, the expression level of miR-206 was not significantly different in the Cx43-plasmid transfected group. In addition, it was found that miR-206 mimics relieved irradiation-induced neuroinflammation, which was confirmed by increased cell viability, and reduced cell apoptosis and cleaved caspase-3 protein expression, as well as decreased inflammatory cytokine secretion. Furthermore, all the effects of miR-206 mimics on γ-radiation-induced astrocytes were reversed by Cx43-plasmid. In summary, the results of the present study indicated that miR-206 may relieve irradiation-induced neural damage by regulating Cx43, which may provide a novel research direction and a potential therapeutic target for the clinical treatment of inflammation-associated neuronal injury following irradiation.

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Connexins—Therapeutic Targets in Cancers

Cited by 20 publications

References 163 publications

Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context

Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context

A Cellular Assay for the Identification and Characterization of Connexin Gap Junction Modulators

MicroRNA‑206 relieves irradiation‑induced neuroinflammation by regulating connexin 43

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