The PI3K/Akt/mTORC signaling axis in head and neck squamous cell carcinoma: Possibilities for therapeutic interventions either as single agents or in combination with conventional therapies

Dilmaghani, Nader Akbari; Safaroghli‐Azar, Ava; Pourbagheri‐Sigaroodi, Atieh; Bashash, Davood

doi:10.1002/iub.2446

Cited by 23 publications

(17 citation statements)

References 204 publications

(411 reference statements)

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“…The PI3K/AKT/mTOR pathway is active in over 80% of HNSCC tumors because of EGFR activation (47%), PIK3CA mutations or amplifications (25%), PIK3R1 overexpression (2%) or PTEN mutation (6%) ( 2 , 89 ). In HNSCC with wild-type PIKCA expression, prolonged tyrosine phosphorylation of PI3K and HER3 recruitment resulted in abnormal PI3K/AKT/mTOR signaling and immune suppression, as shown by an independent kinome-wide siRNA screen.…”

Section: Pten/pi3k/akt/mtormentioning

confidence: 99%

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

Xiao

et al. 2023

Front. Oncol.

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The development of techniques and immunotherapies are widely applied in cancer treatment such as checkpoint inhibitors, adoptive cell therapy, and cancer vaccines apart from radiation therapy, surgery, and chemotherapy give enduring anti-tumor effects. Minority people utilize single-agent immunotherapy, and most people adopt multiple-agent immunotherapy. The difficulties are resolved by including the biomarkers to choose the non-responders’ and responders’ potentials. The possibility of the potential complications and side effects are examined to improve cancer therapy effects. The Head and Neck Squamous Cell Carcinoma (HNSCC) is analyzed with the help of programmed cell death ligand 1 (PD-L1) and Insulin-like growth factor (IGF). But how IGF and PD-L1 upregulation depends on IL-6, EGFR, and LIN28/Let7-related mechanisms are poorly understood. Briefly, IL-6 stimulates gene expressions of IGF-1/2, and IL-6 cross-activates IGF-1R signaling, NF-κB, and STAT3. NF-κB, up-regulating PD-L1 expressions. IL-6/JAK1 primes PD-L1 for STT3-mediated PD-L1 glycosylation, stabilizes PD-L1 and trafficks it to the cell surface. Moreover, ΔNp63 is predominantly overexpressed over TAp63 in HNSCC, elevates circulating IGF-1 levels by repressing IGFBP3, and activates insulin receptor substrate 1 (IRS1).TP63 and SOX2 form a complex with CCAT1 to promote EGFR expression. EGFR activation through EGF binding extends STAT3 activation, and EGFR and its downstream signaling prolong PD-L1 mRNA half-life. PLC-γ1 binding to a cytoplasmic motif of elevated PD-L1 improves EGF-induced activation of inositol 1,4,5-tri-phosphate (IP3), and diacylglycerol (DAG) subsequently elevates RAC1-GTP. RAC1-GTP was convincingly demonstrated to induce the autocrine production and action of IL-6/IL-6R, forming a feedback loop for IGF and PD-L1 upregulation. Furthermore, the LIN28-Let7 axis mediates the NF-κB-IL-6-STAT3 amplification loop, activated LIN28-Let7 axis up-regulates RAS, AKT, IL-6, IGF-1/2, IGF-1R, Myc, and PD-L1, plays pivotal roles in IGF-1R activation and Myc, NF-κB, STAT3 concomitant activation. Therefore, based on a detailed mechanisms review, our article firstly reveals that IL-6, EGFR, and LIN28/Let7-related mechanisms mediate PD-L1 and IGF upregulation in HNSCC, which comprehensively influences immunity, inflammation, metabolism, and metastasis in the tumor microenvironment, and might be fundamental for overcoming therapy resistance.

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Section: Pten/pi3k/akt/mtormentioning

confidence: 99%

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

Xiao

et al. 2023

Front. Oncol.

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“…Studies have demonstrated that PI3K inhibitors represent a therapeutic strategy against HNSC. 53 - 55 Moreover, activation of JAK-STAT signaling contributes to cellular invasion and proliferation in HNSC. 56 , 57 This highlights the tumor aggression-associated role of LIMA1 in patients with HNSC.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of LIMA1 Indicates Poor Prognosis and Promotes Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma

Liao

Gao

et al. 2022

Clin Med Insights Oncol

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Background: LIMA1 encodes LIM domain and actin binding 1, a cytoskeleton-associated protein whose loss has been linked to migration and invasion behavior of cancer cells. However, the roles of LIMA1 underlying the malignant behavior of tumors in head and neck squamous cell carcinoma (HNSC) are not fully understood. Methods: We conducted a multi-omics study on the role of LIMA1 in HNSC based on The Cancer Genome Atlas data. Subsequent in vitro experiments were performed to validate the results of bioinformatic analysis. We first identified the correlation between LIMA1 and tumor cell functional states according to single-cell sequencing data in HNSC. The potential downstream effects of LIMA1 were explored for gene ontology and Kyoto Encyclopedia of Genes and Genomes pathways through functional enrichment analysis of the gene sets that correlated with LIMA1 in HNSC. The prognostic role of LIMA1 was assessed using the log rank test to compare difference in survival between LIMA1High and LIMA1Low patients. Univariate Cox regression and multivariate Cox regression were further carried out to identify the prognostic value of LIMA1 in HNSC. Results: LIMA1 was identified as a prognostic biomarker and is associated with epithelial-mesenchymal transition (EMT) progress in HNSC. In vitro silencing of LIMA1 suppressed EMT and related pathways in HNSC. Conclusions: LIMA1 promotes EMT and further leads to tumor invasion and metastasis. Increased expression of LIMA1 indicates poor survival, identifying it as a prognostic biomarker in HNSC.

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“…These data suggest that a combination of immune checkpoint inhibitors and mTOR inhibitors may be more effective. In fact, many pharmaceutical companies are conducting clinical trials of combinations of PI3K/mTOR inhibitors and immune checkpoint inhibitors [ 97 , 98 , 99 ]. mTOR is required for Th1 and Th2 effector T cell differentiation.…”

Section: Cancer Therapy By Targeting Mtormentioning

confidence: 99%

Targeting mTOR for Anti-Aging and Anti-Cancer Therapy

2023

Molecules

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The balance between anabolism and catabolism is disrupted with aging, with the rate of anabolism being faster than that of catabolism. Therefore, mTOR, whose major function is to enhance anabolism and inhibit catabolism, has become a potential target of inhibition for anti-aging therapy. Interestingly, it was found that the downregulation of the mTOR signaling pathway had a lifespan-extending effect resembling calorie restriction. In addition, the mTOR signaling pathway promotes cell proliferation and has been regarded as a potential anti-cancer target. Rapamycin and rapalogs, such as everolimus, have proven to be effective in preventing certain tumor growth. Here, we reviewed the basic knowledge of mTOR signaling, including both mTORC1 and mTORC2. Then, for anti-aging, we cited a lot of evidence to discuss the role of targeting mTOR and its anti-aging mechanism. For cancer therapy, we also discussed the role of mTOR signaling in different types of cancers, including idiopathic pulmonary fibrosis, tumor immunity, etc. In short, we discussed the research progress and both the advantages and disadvantages of targeting mTOR in anti-aging and anti-cancer therapy. Hopefully, this review may promote more ideas to be generated for developing inhibitors of mTOR signaling to fight cancer and extend lifespan.

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The PI3K/Akt/mTORC signaling axis in head and neck squamous cell carcinoma: Possibilities for therapeutic interventions either as single agents or in combination with conventional therapies

Cited by 23 publications

References 204 publications

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

Mutual connected IL-6, EGFR and LIN28/Let7-related mechanisms modulate PD-L1 and IGF upregulation in HNSCC using immunotherapy

Overexpression of LIMA1 Indicates Poor Prognosis and Promotes Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma

Targeting mTOR for Anti-Aging and Anti-Cancer Therapy

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