A positive feedback loop involving EGFR/Akt/mTORC1 and IKK/NF-κB regulates head and neck squamous cell carcinoma proliferation

Li, Zhipeng; Yang, Zhi-Zheng; Passaniti, Antonino; Lapidus, Rena G.; Li, Xuefeng; Cullen, Kevin J.; Han, Dong

doi:10.18632/oncotarget.7441

Cited by 56 publications

(59 citation statements)

References 58 publications

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“…Nonetheless, a recent report showed that IKK/NF-B activity could be mediated by TSC2 through mTORC1 activation in PTEN-null prostate cancer cells, suggesting that mTORC1 could serve as an upstream modulator for IKK/NF-B activation (54). Another study also reported that mTORC1 activation regulates NF-B activation, which involves upregulation of EGFR and IKK activation, possibly through a positive-feedback loop regulation (55). Feedback mechanisms of downstream events of NF-B activated by LMP1, e.g., EGFR overexpression, may be involved to modulate upstream events, e.g., PI3K/AKT, to induce mTORC1 activation, hence forming a positive-feedback loop in mTORC1/NF-B activation in LMP1-expressing NPC cells to promote tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

Zhang

Jia

Lin

et al. 2017

J Virol

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Accumulating evidence indicates that oncogenic viral protein plays a crucial role in activating aerobic glycolysis during tumorigenesis, but the underlying mechanisms are largely undefined. Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a transmembrane protein with potent cell signaling properties and has tumorigenic transformation property. Activation of NF-B is a major signaling pathway mediating many downstream transformation properties of LMP1. Here we report that activation of mTORC1 by LMP1 is a key modulator for activation of NF-B signaling to mediate aerobic glycolysis. NF-B activation is involved in the LMP1-induced upregulation of glucose transporter 1 (Glut-1) transcription and growth of nasopharyngeal carcinoma (NPC) cells. Blocking the activity of mTORC1 signaling effectively suppressed LMP1-induced NF-B activation and Glut-1 transcription. Interfering NF-B signaling had no effect on mTORC1 activity but effectively altered Glut-1 transcription. Luciferase promoter assay of Glut-1 also confirmed that the Glut-1 gene is a direct target gene of NF-B signaling. Furthermore, we demonstrated that C-terminal activating region 2 (CTAR2) of LMP1 is the key domain involved in mTORC1 activation, mainly through IKK␤-mediated phosphorylation of TSC2 at Ser 939 . Depletion of Glut-1 effectively led to suppression of aerobic glycolysis, inhibition of cell proliferation, colony formation, and attenuation of tumorigenic growth property of LMP1-expressing nasopharyngeal epithelial (NPE) cells. These findings suggest that targeting the signaling axis of mTORC1/NF-B/Glut-1 represents a novel therapeutic target against NPC.IMPORTANCE Aerobic glycolysis is one of the hallmarks of cancer, including NPC. Recent studies suggest a role for LMP1 in mediating aerobic glycolysis. LMP1 expression is common in NPC. The delineation of essential signaling pathways induced by LMP1 in aerobic glycolysis contributes to the understanding of NPC pathogenesis. This study provides evidence that LMP1 upregulates Glut-1 transcription to control aerobic glycolysis and tumorigenic growth of NPC cells through mTORC1/NF-B signaling. Our results reveal novel therapeutic targets against the mTORC1/NF-B/ Glut-1 signaling axis in the treatment of EBV-infected NPC.

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Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

Zhang

Jia

Lin

et al. 2017

J Virol

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“…Additionally, it has been described that chemotherapeutic agents stimulate the activation of nuclear transcription factor NF-κB, thus enhancing chemoresistance mechanisms in cancer cells [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Calebin A Potentiates the Effect of 5-FU and TNF-β (Lymphotoxin α) against Human Colorectal Cancer Cells: Potential Role of NF-κB

Buhrmann

Kunnumakkara

Popper

et al. 2020

IJMS

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Objective: The majority of chemotherapeutic agents stimulate NF-κB signaling that mediates cell survival, proliferation and metastasis. The natural turmeric non-curcuminoid derivate Calebin A has been shown to suppress cell growth, invasion and colony formation in colorectal cancer cells (CRC) by suppression of NF-κB signaling. Therefore, we hypothesized here that Calebin A might chemosensitize the TNF-β-treated tumor cells and potentiates the effect of 5-Fluorouracil (5-FU) in advanced CRC. Materials and Methods: CRC cells (HCT116) and their clonogenic 5-FU chemoresistant counterparts (HCT116R) were cultured in monolayer or alginate-based 3D tumor environment culture and were treated with/without Calebin A, TNF-β, 5-FU, BMS-345541 and DTT (dithiothreitol). Results: The results showed that TNF-β increased proliferation, invasion and resistance to apoptosis in chemoresistant CRC cells. Pretreatment with Calebin A significantly chemosensitized HCT116R to 5-FU and inhibited the TNF-β-induced enhanced efforts for survival, invasion and anti-apoptotic effects. We found further that Calebin A significantly suppressed TNF-β-induced phosphorylation and nuclear translocation of p65-NF-κB, similar to BMS-345541 (specific IKK inhibitor) and NF-κB-induced tumor-promoting biomarkers (NF-κB, β1-Integrin, MMP-9, CXCR4, Ki67). This was associated with increased apoptosis in HCT116 and HCT116R cells. Furthermore, blocking of p65-NF-κB stimulation by Calebin A was imparted through the downmodulation of p65-NF-κB binding to the DNA and this suppression was turned by DTT. Conclusion: Our findings indicate, for the first time, that Calebin A chemosensitizes human CRC cells to chemotherapy by targeting of the p65-NF-κB signaling pathway.

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“…Programmed cell death can be suppressed by the nucleus localization of nuclear factor‐ κ B (NF‐ κ B) , which induces the expression of antiapoptotic factors such as the IAPs, the TRAFs, and Bfl‐1 . NF‐ κ B plays a critical role in chemotherapy resistance due to its ability to reduce apoptosis . Apoptotic pathways are related with the sensitivity of target drugs , and Linsitinib resistance in ESCC may be related to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Overcoming Linsitinib intrinsic resistance through inhibition of nuclear factor‐κB signaling in esophageal squamous cell carcinoma

Chen

Zhang

et al. 2017

Cancer Medicine

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The aim of this study is to evaluate the efficacy of insulin‐like growth factor 1 receptor (IGF‐1R) inhibitor Linsitinib, in esophageal squamous cell carcinoma (ESCC), and to characterize special biomarker to screen Linsitinib‐sensitive patients as well as explore the molecular‐resistant mechanism to Linsitinib in ESCC. Our study evaluated the sensitivity of insulin‐like growth factor 1 receptor (IGF‐1R) inhibitor, Linsitinib in ESCC cells with MTT assay. After Linsitinib treatment, the expressions of downstream signaling molecules and apoptosis pathways were measured by western blot. And the antitumor effect of Linsitinib and JSH‐23, an inhibitor of nuclear factor‐κB transcriptional activity, was analyzed both as single agent and in combination in ESCC. Apoptosis, cell viability, and clonogenic survival analysis were also investigated. The sensitivity of Linsitinib was relatively variable in patient‐derived primary ESCC cells as well as in human commercial cell lines. And the downstream AKT/mTOR and ERK signaling pathways were inhibited by Linsitinib, while phosphorylation level of NF‐κB p65 was obviously activated to reduce apoptosis effect in Linsitinib‐resistant cell lines. Most importantly, blockage of NF‐κB activity by JSH‐23 could sensitize resistant cells to Linsitinib treatment. Results from this study demonstrated that the intrinsic resistance to Linsitinib was predominantly mediated by NF‐κB activation in ESCC. Moreover, combination of Linsitinib and JSH‐23 as therapy provides a novel strategy to overcome resistance to Linsitinib in ESCC.

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A positive feedback loop involving EGFR/Akt/mTORC1 and IKK/NF-κB regulates head and neck squamous cell carcinoma proliferation

Cited by 56 publications

References 58 publications

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

Calebin A Potentiates the Effect of 5-FU and TNF-β (Lymphotoxin α) against Human Colorectal Cancer Cells: Potential Role of NF-κB

Overcoming Linsitinib intrinsic resistance through inhibition of nuclear factor‐κB signaling in esophageal squamous cell carcinoma

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