Molecular insights: Suppression of EGFR and AKT activation by a small molecule in non-small cell lung cancer

Chandrasekaran, Balaji; Tyagi, Ashish; Sharma, Arun; Cai, Lu; Ankem, Murali K.; Damodaran, Chendil

doi:10.18632/genesandcancer.154

Cited by 15 publications

(8 citation statements)

References 43 publications

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“…Successful penetration of the BBB by meningitis-causing bacterial pathogens requires four prerequisites: a high level of bacteremia, bacterial adhesion and invasion of BMECs, actin cytoskeleton rearrangement, and bacterial vitality maintenance (Kim, 2002, 2008; Kim et al, 2005; Coureuil et al, 2017); all of which are complex bacteria-host interactions involving multiple host molecules. EGFR is a host factor that has been found to play essential roles in several bacterial infections recently, although it was widely reported previously to be associated with different cancers (Mikami et al, 2005; Yan et al, 2009; Adams et al, 2017; Araki et al, 2017; Chandrasekaran et al, 2017; Dheeraj et al, 2017). For instance, H. pylori was shown to induce EGFR transactivation in gastric epithelial cells, resulting in the upregulation of MMP10 and extracellular matrix disorder (Yan et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Transactivated Epidermal Growth Factor Receptor Recruitment of α-actinin-4 From F-actin Contributes to Invasion of Brain Microvascular Endothelial Cells by Meningitic Escherichia coli

Yang

et al. 2019

Front. Cell. Infect. Microbiol.

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Bacterial penetration of the blood-brain barrier requires its successful invasion of brain microvascular endothelial cells (BMECs), and host actin cytoskeleton rearrangement in these cells is a key prerequisite for this process. We have reported previously that meningitic Escherichia coli can induce the activation of host's epidermal growth factor receptor (EGFR) to facilitate its invasion of BMECs. However, it is unknown how EGFR specifically functions during this invasion process. Here, we identified an important EGFR-interacting protein, α-actinin-4 (ACTN4), which is involved in maintaining and regulating the actin cytoskeleton. We observed that transactivated-EGFR competitively recruited ACTN4 from intracellular F-actin fibers to disrupt the cytoskeleton, thus facilitating bacterial invasion of BMECs. Strikingly, this mechanism operated not only for meningitic E. coli, but also for infections with Streptococcus suis, a Gram-positive meningitis-causing bacterial pathogen, thus revealing a common mechanism hijacked by these meningitic pathogens where EGFR competitively recruits ACTN4. Ever rising levels of antibiotic-resistant bacteria and the emergence of their extended-spectrum antimicrobial-resistant counterparts remind us that EGFR could act as an alternative non-antibiotic target to better prevent and control bacterial meningitis.

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Section: Discussionmentioning

confidence: 99%

Transactivated Epidermal Growth Factor Receptor Recruitment of α-actinin-4 From F-actin Contributes to Invasion of Brain Microvascular Endothelial Cells by Meningitic Escherichia coli

Yang

et al. 2019

Front. Cell. Infect. Microbiol.

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“…Akt, a canonical downstream effector of the EGFR pathway, is important for BoHV-1 infection in MDBK cells [35][36][37], but its role during virus infection in A549 cells has been unknown. To address this question, we initially detected whether Akt signaling was activated in BoHV-1-infected A549 cells.…”

Section: The Activation Of Akt Signaling In Bohv-1-infected A549 Cellmentioning

confidence: 99%

The Role of Epidermal Growth Factor Receptor Signaling Pathway during Bovine Herpesvirus 1 Productive Infection in Cell Culture

Qiu

Chang

et al. 2020

Viruses

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Accumulating studies have shown that the epidermal growth factor receptor (EGFR) signaling pathway plays an essential role in mediating cellular entry of numerous viruses. In this study, we report that bovine herpesvirus 1 (BoHV-1) productive infection in both the human lung carcinoma cell line A549 and bovine kidney (MDBK) cells leads to activation of EGFR, as demonstrated by the increased phosphorylation of EGFR at Tyr1068 (Y1068), which in turn plays important roles in virus infection. A time-of-addition assay supported that virus replication at post-entry stages was affected by the EGFR specific inhibitor Gefitinib. Interestingly, both phospholipase C-γ1 (PLC-γ1) and Akt, canonical downstream effectors of EGFR, were activated following virus infection in A549 cells, while Gefitinib could inhibit the activation of PLC-γ1 but not Akt. In addition, virus titers in A549 cells was inhibited by chemical inhibition of PLC-γ1, but not by the inhibition of Akt. However, the Akt specific inhibitor Ly294002 could significantly reduce the virus titer in MDBK cells. Taken together, our data suggest that PLC-γ1 is stimulated in part through EGFR for efficient replication in A549 cells, whereas Akt can be stimulated by virus infection independent of EGFR, and is not essential for virus productive infection, indicating that Akt modulates BoHV-1 replication in a cell type-dependent manner. This study provides novel insights on how BoHV-1 infection activates EGFR signaling transduction to facilitate virus replication.

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“…There is increasing evidence to suggest that β-catenin is upregulated in NSCLC tumor cells when compared to normal cells. It has been shown that activation of the β-catenin pathway stimulates proliferation and leads to the generation and development of NSCLC 35,36 . In the present study, we showed that AS-IV inhibited the Akt phosphorylation and subsequent GSK-3β function, which in turn stimulated the ubiquitination of β-catenin.…”

Section: Discussionmentioning

confidence: 99%

Astragaloside IV Inhibits the Progression of Non-Small Cell Lung Cancer Through the Akt/GSK-3β/β-Catenin Pathway

Jia

Lv²,

Zhang

et al. 2019

oncol res

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Astragaloside IV (AS-IV) is an active ingredient in Astragalus membranaceus, and involved in various biological processes, such as regulating the immune system, and counteracting inflammation and malignancy. The aim of this study was to explore the effect of AS-IV on non-small cell lung cancer (NSCLC) cells. A cell counting kit (CCK)-8 assay and flow cytometry were performed to investigate cell survival and cell death, and Western blotting was performed to assess protein expression. We found that AS-IV inhibited the migration and proliferation of NSCLC cells, and caused a noticeable increase in cell death. Furthermore, the expression of Bax, a marker of cell death, was increased, while the expression of Bcl-2, an anti-apoptotic protein, was reduced. AS-IV also promoted cleavage of caspase-3, another indication of apoptosis. Finally, the Akt/GSK-3β/β-catenin axis was suppressed in response to AS-IV. Taken together, these findings provide evidence that AS-IV inhibits NSCLC development via inhibition of the Akt/GSK-3β/β-catenin signaling axis. We therefore propose that AS-IV represents a promising novel agent for the treatment of NSCLC.

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Molecular insights: Suppression of EGFR and AKT activation by a small molecule in non-small cell lung cancer

Cited by 15 publications

References 43 publications

Transactivated Epidermal Growth Factor Receptor Recruitment of α-actinin-4 From F-actin Contributes to Invasion of Brain Microvascular Endothelial Cells by Meningitic Escherichia coli

Transactivated Epidermal Growth Factor Receptor Recruitment of α-actinin-4 From F-actin Contributes to Invasion of Brain Microvascular Endothelial Cells by Meningitic Escherichia coli

The Role of Epidermal Growth Factor Receptor Signaling Pathway during Bovine Herpesvirus 1 Productive Infection in Cell Culture

Astragaloside IV Inhibits the Progression of Non-Small Cell Lung Cancer Through the Akt/GSK-3β/β-Catenin Pathway

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