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Mapping the anti-cancer activity of α-connexin carboxyl-terminal (aCT1) peptide in resistant HER2+ breast cancer

ABSTRACT: This study aims to examine the mechanisms for the anti-cancer effects of a therapeutic peptide agent targeted to connexin 43 (Cx43) called alpha-connexin carboxyl-terminal peptide (aCT1). Findings from this study identify the effect of aCT1 on breast cancer signaling using a resistant HER2+ breast cancer cell line.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250543 | GEO | 2023/12/20

REPOSITORIES: GEO

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Mapping the anti-cancer activity of alpha-connexin carboxyl-terminal (aCT1) peptide in resistant HER2+ breast cancer

Project description:Connexin 43 (Cx43) is a protein encoded by the GJA1 gene and is a component of cell membrane structures called gap junctions, which facilitate intercellular communication. Prior evidence indicates that elevated GJA1 expression in the HER2-positive (HER2+) subtype of breast cancer is associated with poor prognosis. Prior evidence also suggests that HER2+ breast cancers that have become refractory to HER2 targeted agents have a loss of Cx43 gap junction intercellular communication (GJIC). In this study, a Cx43 targeted agent called alpha-connexin carboxyl-terminal peptide (aCT1) is examined to determine whether GJIC can be rescued in refractory HER2+ breast cancer cells. A proposed mechanism of action for aCT1 is binding to the tight junction protein Zonal Occludens-1 (ZO-1). However, the true scope of activity for aCT1 has not been explored. In this study, proteomic analysis is used to determine the breadth of aCT1 interacting proteins. The NanoString nCounter Breast Cancer 360 panel was also used to examine the effect of aCT1 on cancer signaling in HER2+ breast cancer cells. Findings from this study show a dynamic range of binding partners for aCT1, many of which regulate gene expression and RNA biology. nCounter analysis shows that a number of pathways are significantly impacted by aCT1 including upregulation of apoptotic factors, leading to the prediction and demonstration that aCT1 can boost the cell death effects of cisplatin and lapatinib in HER2+ breast cancer cells that have become resistant to HER2 targeted agents.

2023-12-01 | MSV000093550 | MassIVE

Mapping the anti-cancer activity of α-connexin carboxyl-terminal (aCT1) peptide in resistant HER2+ breast cancer

Project description:Mapping the anti-cancer activity of α-connexin carboxyl-terminal (aCT1) peptide in resistant HER2+ breast cancer

| PRJNA1054510 | ENA

Sertoli cell specific testicular gene expression of Connexin 43 knockout mice

Project description:Infertility observed in adult Sertoli cell (SC)-specific Connexin 43 Knockout-mice rather seems to be an effect of the disturbed SC-Germ cell (GC) crosstalk than a direct consequence of the loss of Cx43 protein in SC with important GC specific genes being mostly affected by this deletion. Identification of differentially expressed genes in testis of cx43 KO-mice at developmental stage 8 days post partum when compared with testis of WT-mice

2011-01-06 | E-GEOD-23431 | biostudies-arrayexpress

Osteocyte Connexin 43 Hemichannels Influence Bone Marrow Mesenchymal Stromal Cell Fate through Prostagladin E2

Project description:Inhibiting Connexin 43 (Cx43) hemichannels in osteocytes led to a significant increase in adipogenesis and a decrease in osteogenesis in bone marrow mesenchymal stromal cells.

2024-12-16 | GSE252059 | GEO

Co-IP (AP-MS) of Connexin-43 - Gap junction protein Connexin-43 is a direct transcriptional regulator of N-cadherin in vivo

Project description:Co-IP Experiment Bait: Cx43-Flag Cell line: Hela Related Publication: Gap Junction protein Connexin-43 is a direct transcriptional regulator of N-cadherin in vivo, Maria Kotini, Elias Barriga, Jonathan Leslie, Marc Gentzel, Verena Rauschenberger, Alexandra Schambony, and Roberto Mayor

2018-10-16 | PXD010870 | Pride

Act1 modulates mRNA metabolism upon IL-17 stimulation

Project description:The IL-17 receptor adaptor molecule Act1, an RNA binding protein, plays a critical role in IL-17-mediated cancer progression. Here we report a novel mechanism for how IL-17/Act1 induces chemoresistance by modulating redox homeostasis through epitranscriptomic regulation of antioxidant RNA metabolism. Transcriptome-wide mapping of direct Act1-RNA interactions revealed that Act1 binds to the 5'UTR of antioxidant mRNAs and Wilms' tumor 1-associating protein (WTAP), a key regulator in m6A methyltransferase complex. Strikingly, Act1's binding sites are located in proximity to m6A modification sites, which allows Act1 to promote the recruitment of elF3G for cap-independent translation. Loss of Act1’s RNA binding activity or Wtap knockdown abolished IL-17-induced m6A modification and translation of Wtap and antioxidant mRNAs, indicating a feedforward mechanism of Act1-WTAP loop. We then developed antisense oligonucleotides (Wtap ASO) that specifically disrupts Act1’s binding to Wtap mRNA, abolishing IL-17/Act1-WTAP-mediated antioxidant protein production during chemotherapy. Wtap ASO substantially increased the antitumor efficacy of cisplatin, demonstrating a potential therapeutic strategy for chemoresistance.

2024-06-06 | GSE263835 | GEO

Sertoli cell specific testicular gene expression of Connexin 43 knockout mice

2011-01-06 | GSE23431 | GEO

Connexin 43 dephosphorylation mediates the Dchs1/YAP/TEAD signaling pathway to impact cardiac fibrosis

Project description:The gap junction protein connexin 43 (Cx43) has been implicated in the development of cardiac fibrosis. We found that Cx43 dephosphorylation at serine 282 (S282) is related to cardiomyocyte apoptosis and arrhythmias in hearts damaged by ischemia/reperfusion. Here, we investigated the effect of Cx43 S282 phosphorylation on fibrosis. We found a decrease in Cx43 S282 phosphorylation in transforming growth factor beta-1 (TGF-β)-induced fibrosis in fibroblasts and an angiotensin II-induced rat model. We transferred a lentivirus with S282A (alanine) into cardiac fibroblasts and an adenovirus with S282A into the hearts of rats. We found that the Cx43 S282A mutation caused fibrosis in cardiac fibroblasts and in the hearts of rats, which suggested that the phosphorylation of Cx43 S282 is important in the development of fibrosis. Furthermore, mRNA sequencing showed that Cx43 dephosphorylation at S282 increased the expression of Dchs1, and Dchs1 inhibited Yes-associated protein (YAP) phosphorylation, subsequently activating the YAP/TEAD signaling pathway and increasing the development of fibrosis. This study suggests that the phosphorylation of Cx43 S282 could be an effective antifibrotic target in cardiac fibroblasts, indicating a novel mechanism and a molecular target that might be promising for the treatment of cardiac fibrosis.

2024-11-28 | GSE249368 | GEO

Implantation Failure of Blastocysts Derived from Oocyte-directed Connexin 43 depleted Mice is Associated with Impaired Ribosomal and Translational Machinery Gene Expression

Project description:Oocyte quality is a well- established determinant of embryonic fate. However, the molecular participants and biological markers that affect and predict adequate embryonic development are largely elusive. We have previously reported that oocyte- directed Connexin 43 (Cx43) depletion leads to embryo implantation defects, although both the morphology of the oocyte and processes presiding embryo implantation appear to undergo normally. In the context of previous data determining Cx43 indispensability to oocyte and embryonic development, we show here that the timing of Cx43 depletion from the oocyte and the ovarian follicle is crucial in determining the severity of subsequent embryonic defects. Specifically, we show that the implantation defects of blastocysts resulting from oocyte- directed Cx43- depleted follicles (depletion occurs at day 3 postnatal), is not due to maternal luteal insufficiency but rather depends solely on the defective blastocysts. Gene expression microarray analysis revealed global defects in the expression of ribosomal proteins, translation initiation factors and other genes associated with cellular biosynthetic and metabolic processes in these defective oocytes and specifically blastocysts. We therefore propose that timely expression of Cx43 in the oocyte and ovarian follicles is a major determinant of oocyte developmental competence, by determining the ability of the resulting blastocyst to facilitate biomass expansion and undergo adequate embryo implantation To study the effect of CX43 on the transcriptom of the pre implantation stages, we compared CX43 KO oocytes to the WT oocytes in three different stages of the very early development. First comparison MII oocytes, second comparison blastocysts, third comparison implantation site.

2013-01-01 | E-GEOD-35299 | biostudies-arrayexpress

Astroglial Connexin 43 sets the blood brain barrier immune quiescence

Project description:In the brain, a unique homeostatic equilibrium strictly controls immune reactions. In healthy conditions, the immune system poorly communicates with the central nervous system (CNS), immune cell migration across the blood brain barrier (BBB) is kept at a very low level and the unique CNS microenvironment strictly restricts immune reactions. Here, we identified the astroglial gap junction protein Connexin 43 has a new actor of this homeostasis. We showed that genetic inactivation of astroglial Cx43 in the mouse induces expression of a specific set of chemokines and endothelial adhesion molecules leading to neutrophils, macrophages, B and T lymphocytes and mature plasmocytes infiltration at the BBB, and to the development of antigen presentation-related mechanisms, in sterile conditions. Thus, astroglial Cx43 by decreasing the expression of leukocytes adhesion and migration mediators, promotes the immune quiescence of the BBB

2015-03-16 | GSE54458 | GEO

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