scholarly journals Connexin 43 confers chemoresistance through activating PI3K

Oncogenesis ◽  
2022 ◽  
Vol 11 (1) ◽  
Author(s):  
Kevin J. Pridham ◽  
Farah Shah ◽  
Kasen R. Hutchings ◽  
Kevin L. Sheng ◽  
Sujuan Guo ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Connexin 43 ◽  
Therapeutic Potential ◽  
Mrna Levels ◽  
Phosphatidylinositol 3 Kinase ◽  
Junction Protein ◽  
Gap Junction Protein ◽  
Cx43 Mrna

AbstractCircumventing chemoresistance is crucial for effectively treating cancer including glioblastoma, a lethal brain cancer. The gap junction protein connexin 43 (Cx43) renders glioblastoma resistant to chemotherapy; however, targeting Cx43 is difficult because mechanisms underlying Cx43-mediated chemoresistance remain elusive. Here we report that Cx43, but not other connexins, is highly expressed in a subpopulation of glioblastoma and Cx43 mRNA levels strongly correlate with poor prognosis and chemoresistance in this population, making Cx43 the prime therapeutic target among all connexins. Depleting Cx43 or treating cells with αCT1–a Cx43 peptide inhibitor that sensitizes glioblastoma to the chemotherapy temozolomide–inactivates phosphatidylinositol-3 kinase (PI3K), whereas overexpression of Cx43 activates this signaling. Moreover, αCT1-induced chemo-sensitization is counteracted by a PI3K active mutant. Further research reveals that αCT1 inactivates PI3K without blocking the release of PI3K-activating molecules from membrane channels and that Cx43 selectively binds to the PI3K catalytic subunit β (PIK3CB, also called PI3Kβ or p110β), suggesting that Cx43 activates PIK3CB/p110β independent of its channel functions. To explore the therapeutic potential of simultaneously targeting Cx43 and PIK3CB/p110β, αCT1 is combined with TGX-221 or GSK2636771, two PIK3CB/p110β-selective inhibitors. These two different treatments synergistically inactivate PI3K and sensitize glioblastoma cells to temozolomide in vitro and in vivo. Our study has revealed novel mechanistic insights into Cx43/PI3K-mediated temozolomide resistance in glioblastoma and demonstrated that targeting Cx43 and PIK3CB/p110β together is an effective therapeutic approach for overcoming chemoresistance.

scholarly journals Connexin 43 confers chemoresistance through activating PI3K

2020 ◽  
Author(s):  
Kevin J Pridham ◽  
Farah Shah ◽  
Kevin L Sheng ◽  
Sujuan Guo ◽  
Min Liu ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Carboxyl Terminus ◽  
Phosphatidylinositol 3 Kinase ◽  
Poor Patient ◽  
Junction Protein ◽  
Gap Junction Protein ◽  
Targeting Peptide ◽  
Patient Prognosis

ABSTRACTCircumventing chemoresistance is crucial for effectively treating glioblastoma due to limited therapeutic options. The gap junction protein connexin 43 (Cx43) renders glioblastoma resistant to the frontline chemotherapy temozolomide; however, targeting Cx43 is difficult because mechanisms underlying Cx43-mediated chemoresistance remain elusive. Here we show that Cx43, but not other connexins, is highly expressed in glioblastoma and strongly correlates with poor patient prognosis and chemoresistance, making Cx43 the prime therapeutic target among all connexins. The intracellular carboxyl terminus of Cx43 binds to phosphatidylinositol 3-kinase (PI3K) catalytic subunit β (PIK3CB, also called PI3Kβ or p110β), thereby activating PI3K signaling independent of Cx43-channels and subsequently inducing temozolomide resistance. A combination of αCT1, a Cx43-targeting peptide inhibitor, and PIK3CB-selective inhibitors restores temozolomide sensitivity in vitro and in vivo. This study not only reveals novel mechanistic insights into chemoresistance in glioblastoma, but also demonstrates that targeting Cx43 and PIK3CB/p110β is an effective approach for overcoming chemoresistance.

Wogonin induces G1 phase arrest through inhibiting Cdk4 and cyclin D1 concomitant with an elevation in p21Cip1 in human cervical carcinoma HeLa cells

2009 ◽  
Vol 87 (6) ◽  
pp. 933-942 ◽  
Author(s):  
Li Yang ◽  
Hai-wei Zhang ◽  
Rong Hu ◽  
Yong Yang ◽  
Qi Qi ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Cervical Carcinoma ◽  
Hela Cells ◽  
Therapeutic Potential ◽  
P53 Gene ◽  
Mrna Levels ◽  
Human Cervical Carcinoma ◽  
Phase Arrest

Wogonin, a naturally occurring flavonoid, has been shown to have tumor therapeutic potential both in vitro and in vivo. To better understand its anticancer mechanism, we examined the effect of wogonin on human cervical carcinoma HeLa cells. In this study, we observed that G1 phase arrest was involved in wogonin-induced growth inhibition in HeLa cells. Over a 24 h exposure of HeLa cells to 90 µmol·L–1 wogonin, the promoters of G1–S transition, including cyclin D1/Cdk4 and pRb, decreased within 12 h and E2F-1 depleted in the nucleus at the same time. As the G1 phase arrest developed, p53 and the Cdk inhibitor p21Cip1 elevated both at protein and mRNA levels. Furthermore, the up-regulation of p21Cip1 induced by wogonin was dramatically inhibited by siRNA-mediated p53 gene silencing. Collectively, our data suggested that wogonin induced G1 phase arrest in HeLa cells by modulating several key G1 regulatory proteins, such as Cdk4 and cyclin D1, as well as up-regulation of a p53-midiated p21Cip1 expression. This mechanism of wogonin may play an important role in the killing of cancerous cells and offer a potential mechanism for its anticancer action in vivo.

scholarly journals Prognostic and Therapeutic Potential of The OIP5 Network in Papillary Renal Cell Carcinoma

2021 ◽  
Author(s):  
Mathilda Chow ◽  
Yan Gu ◽  
Lizhi He ◽  
Xiaozeng Lin ◽  
Ying Dong ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Papillary Renal Cell Carcinoma ◽  
Mrna Levels ◽  
Rna Seq

Abstract Background: Papillary renal cell carcinoma (pRCC) is an aggressive but minor type of RCC compared to the main RCC type, clear cell RCC. The current understanding and management of pRCC remain poor. OIP5 possesses oncogenic functions; its contributions to pRCC remain unknown.Methods: OIP5 expression in pRCC at both the protein and mRNA levels was determined using tissue microarray and TCGA dataset. OIP5 was ectopically expressed in metastatic ACHN pRCC cells; xenografts were performed with gene expression profiled by RNA-seq. Differentially expressed genes (DEGs) were analyzed for prognostic potential and impact on pRCC. The effect of PLK1, an OIP5-related DEG, on pRCC tumor growth in vivo was examined.Results: OIP5 expression is upregulated in pRCC. The upregulation associates with pRCC adverse features (T1P<T2P<CIMP, Stage1+2<Stage 3<Stage 4, and N0<N1) and effectively stratifies the fatality risk. OIP5 promotes ACHN pRCC cell proliferation and xenograft formation. RNA-seq reveals network alterations related to immune regulation, metabolism, and hypoxia in ACHN OIP5 tumors compared to empty vector tumors. A set of DEGs was derived from ACHN OIP5 xenografts and primary pRCCs (n=282) contingent to OIP5 upregulation; both DEG sets share 66 overlap genes. Overlap66 effectively predicts overall survival (p<2e-16) and relapse (p<2e-16) possibilities. The prediction is associated with a good out-of-sample performance, supporting its clinical applications. High-risk tumors stratified by Overlap66 risk score possess an immune suppressive environment, evident by elevations in Treg cells and PD1 expression in CD8 T cells. Upregulation of PLK1 occurs in both xenografts and primary pRCC tumors with OIP5 elevations. PLK1 displays a synthetic lethality relationship with OIP5; PLK1 inhibitor BI2356 causes G2/M arrest in ACHN OIP5 cells in vitro and significantly inhibits the growth of xenografts formed by ACHN OIP5 cells in vivo. Conclusions: Our research reveals that OIP5 and its network possess robust prognostic and therapeutic potentials; the prognostic value of Overlap66 and the therapeutic potential of PLK1 inhibitors may pave the way for developing personalized medicine for pRCC management.

ID: 129: PARTICULATE MATTER DISRUPTS ENDOTHELIAL CELL PERMEABILITY VIA GAP JUNCTION PROTEIN

2016 ◽  
Vol 64 (4) ◽  
pp. 970.2-971
Author(s):  
X Wu ◽  
X Xu ◽  
JG Garcia ◽  
T Wang
Keyword(s):  
Signal Transduction ◽  
Particulate Matter ◽  
Endothelial Cell ◽  
Gap Junction ◽  
Cell Permeability ◽  
Mrna Levels ◽  
Barrier Integrity ◽  
Junction Protein ◽  
Gap Junction Protein ◽  
Cx43 Mrna

IntroductionParticulate matter (PM) is significantly associated with cardiopulmonary morbidity and mortality. We previously demonstrated that PM induces endothelial barrier disruption via reactive oxygen species (ROS)-dependent mechanisms. This study is focused on characterization of PM-regulated endothelial dysfunction via connexin43 (Cx43), a Gap junction protein. Gap junction is designated as intercellular channel which allows cells to communicate with each other, share nutrients, and transfer chemical or electrical signals, in turn, enables cells in a tissue to function in a coordinated manner.Methods and ResultsCx43 protein levels were evaluated by western blotting, and band density quantified using MyImageAnalysis. Real-time PCR was conducted to determine Cx43 mRNA levels. Human pulmonary artery endothelial cell (EC) barrier function was measured using the electrical cell-substrate impedance sensing (ECIS) system (Applied Biophysics) that provides a readout of transendothelial electrical resistance (TER). PM sample (0.1–0.3 µm of aerodynamic diameter) was collected (April of 2005) from the Ft. McHenry Tunnel, Baltimore, MD using a high-volume cyclone collector. PM (100 µg/ml) induced time-dependent increases in EC Cx43 mRNA levels (∼5 fold increase at 4 hr) and protein expression which was attenuated by N-acetyl-cysteine (NAC, 5 mM, 1 hr pretreatment), an ROS scavenger. Unlike Cx43, Cx37, another connexin expressed in ECs, remained unaltered by PM challenge. In addition, EC pretreatment with a Cx43 inhibitor, connexin-mimetic peptide Gap27 (500 µM, 2 hr pretreatment), significantly attenuated PM-reduced TER reduction by 45%, suggesting a central role of Cx43 in PM-induced lung EC barrier integrity disruption and signal transduction.ConclusionsOur results suggest Cx43 as a key and novel participant in PM-mediated signal transduction that results in loss of vascular barrier integrity. Cx43 may serve as a therapeutic target in PM-induced cardiopulmonary toxicities.

scholarly journals Hyperglycemia downregulates Connexin36 in pancreatic islets via the upregulation of ICER-1/ICER-1γ

2013 ◽  
Vol 51 (1) ◽  
pp. 49-58 ◽  
Author(s):  
Jacques-Antoine Haefliger ◽  
Françoise Rohner-Jeanrenaud ◽  
Dorothée Caille ◽  
Anne Charollais ◽  
Paolo Meda ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Chronic Exposure ◽  
Prolonged Exposure ◽  
Mrna Levels ◽  
Adult Rats ◽  
Junction Protein ◽  
And Function

Channels formed by the gap junction protein Connexin36 (CX36) contribute to the proper control of insulin secretion. We previously demonstrated that chronic exposure to glucose decreases Cx36 levels in insulin-secreting cells in vitro. Here, we investigated whether hyperglycemia also regulates Cx36 in vivo. Using a model of continuous glucose infusion in adult rats, we showed that prolonged (24–48 h) hyperglycemia reduced the Cx36 gene Gjd2 mRNA levels in pancreatic islets. Accordingly, prolonged exposure to high glucose concentrations also reduced the expression and function of Cx36 in the rat insulin-producing INS-1E cell line. The glucose effect was blocked after inhibition of the cAMP/PKA pathway and was associated with an overexpression of the inducible cAMP early repressor ICER-1/ICER-1γ, which binds to a functional cAMP-response element in the promoter of the Cx36 gene Gjd2. The involvement of this repressor was further demonstrated using an antisense strategy of ICER-1 inhibition, which prevented glucose-induced downregulation of Cx36. The data indicate that chronic exposure to glucose alters the in vivo expression of Cx36 by the insulin-producing β-cells through ICER-1/ICER-1γ overexpression. This mechanism may contribute to the reduced glucose sensitivity and altered insulin secretion, which contribute to the pathophysiology of diabetes.

scholarly journals Deacetyl Ganoderic Acid F Inhibits LPS-Induced Neural Inflammation via NF-κB Pathway Both In Vitro and In Vivo

Nutrients ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 85 ◽  
Author(s):  
Feiya Sheng ◽  
Lele Zhang ◽  
Songsong Wang ◽  
Lele Yang ◽  
Peng Li
Keyword(s):  
Inflammatory Cytokines ◽  
Nuclear Translocation ◽  
Therapeutic Potential ◽  
Serum Levels ◽  
No Production ◽  
Mrna Levels ◽  
Mice Model ◽  
Ganoderic Acid

Microglia mediated neuronal inflammation has been widely reported to be responsible for neurodegenerative disease. Deacetyl ganoderic acid F (DeGA F) is a triterpenoid isolated from Ganoderma lucidum, which is a famous edible and medicinal mushroom used for treatment of dizziness and insomnia in traditional medicine for a long time. In this study the inhibitory effects and mechanisms of DeGA F against lipopolysaccharide (LPS)-induced inflammation both in vitro and in vivo were investigated. On murine microglial cell line BV-2 cells, DeGA F treatment inhibited LPS-triggered NO production and iNOS expression and affected the secretion and mRNA levels of relative inflammatory cytokines. DeGA F inhibited LPS-induced activation of the NF-κB pathway, as evidenced by decreased phosphorylation of IKK and IκB and the nuclear translocation of P65. In vivo, DeGA F treatment effectively inhibited NO production in zebrafish embryos. Moreover, DeGA F suppressed the serum levels of pro-inflammatory cytokines, including TNF-α and IL-6 in LPS-stimulated mice model. DeGA F reduced inflammatory response by suppressing microglia and astrocytes activation and also suppressed LPS-induced NF-κB activation in mice brains. Taken together, DeGA F exhibited remarkable anti-inflammatory effects and promising therapeutic potential for neural inflammation associated diseases.

scholarly journals Novel Therapeutic Insights in Dedifferentiated Liposarcoma: A Role for FGFR and MDM2 Dual Targeting

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3058
Author(s):  
Bérengère Dadone-Montaudié ◽  
Audrey Laroche-Clary ◽  
Aline Mongis ◽  
Emmanuel Chamorey ◽  
Ilaria Di Mauro ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Therapeutic Potential ◽  
Dedifferentiated Liposarcoma ◽  
Mdm2 Antagonist ◽  
Dual Targeting ◽  
Promising Strategy ◽  
Disease Stabilization ◽  
Well Differentiated

We aimed to evaluate the therapeutic potential of the pan-FGFR inhibitor erdafitinib to treat dedifferentiated liposarcoma (DDLPS). FGFR expression and their prognostic value were assessed in a series of 694 samples of well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). The effect of erdafitinib—alone or in combination with other antagonists—on tumorigenicity was evaluated in vitro and in vivo. We detected overexpression of FGFR1 and/or FGFR4 in a subset of WDLPS and DDLPS and demonstrated correlation of this expression with poor prognosis. Erdafitinib treatment reduced cell viability, inducing apoptosis and strong inhibition of the ERK1/2 pathway. Combining erdafitinib with the MDM2 antagonist RG7388 exerted a synergistic effect on viability, apoptosis, and clonogenicity in one WDLPS and two DDLPS cell lines. Efficacy of this combination was confirmed in vivo on a DDLPS xenograft. Importantly, we report the efficacy of erdafitinib in one patient with refractory DDLPS showing disease stabilization for 12 weeks. We provide evidence that the FGFR pathway has therapeutic potential for a subset of DDLPS and that an FGFR1/FGFR4 expression might constitute a powerful biomarker to select patients for FGFR inhibitor clinical trials. In addition, we show that combining erdafitinib with RG7388 is a promising strategy for patients with DDLPS that deserves further investigation in the clinical setting.

scholarly journals Ezrin-anchored PKA phosphorylates serine 369 and 373 on connexin 43 to enhance gap junction assembly, communication, and cell fusion

2018 ◽  
Vol 475 (2) ◽  
pp. 455-476 ◽  
Author(s):  
Aleksandra R. Dukic ◽  
Pascale Gerbaud ◽  
Jean Guibourdenche ◽  
Bernd Thiede ◽  
Kjetil Taskén ◽  
...  
Keyword(s):  
Gap Junction ◽  
Cell Fusion ◽  
Connexin 43 ◽  
Phosphorylation Sites ◽  
Peptide Arrays ◽  
Signaling Complex ◽  
Gap Junction Communication ◽  
Junction Protein ◽  
Gap Junction Protein

A limited number of human cells can fuse to form multinucleated syncytia. In the differentiation of human placenta, mononuclear cytotrophoblasts fuse to form an endocrinologically active, non-proliferative, multinucleated syncytium. This syncytium covers the placenta and manages the exchange of nutrients and gases between maternal and fetal circulation. We recently reported protein kinase A (PKA) to be part of a macromolecular signaling complex with ezrin and gap junction protein connexin 43 (Cx43) that provides cAMP-mediated control of gap junction communication. Here, we examined the associated phosphorylation events. Inhibition of PKA activity resulted in decreased Cx43 phosphorylation, which was associated with reduced trophoblast fusion and differentiation. In vitro studies using peptide arrays, together with mass spectrometry, pointed to serine 369 and 373 of Cx43 as the major PKA phosphorylation sites that increases gap junction assembly at the plasmalemma. A combination of knockdown and reconstitution experiments and gap-fluorescence loss in photobleaching assays with mutant Cx43 containing single or double phosphoserine-mimicking amino acid substitutions in putative PKA phosphorylation sites demonstrated that phosphorylation of S369 and S373 mediated gap junction communication, trophoblast differentiation, and cell fusion.

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