Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells

Li, Xiaodong; Chen, Fang; Zhu, Qiuhua; Ding, Bingjie; Zhong, Qingxiu; Huang, Kaikai; Jiang, Xuejie; Wang, Zhixiang; Chen, Yin; Zhu, Yujie; Li, Zhen; Fang, Meng

doi:10.18632/oncotarget.8844

Cited by 61 publications

(50 citation statements)

References 43 publications

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“…The failure in using AKT inhibitors as a single agent for cancer treatment prompted us to test whether they can be applied in combination therapy. In fact, AKT pathway alterations have been implicated in radioresistance in many types of cancer, including head and neck cancer, prostate cancer, glioblastoma, and acute myeloid leukemia [4,9,[21][22][23][24][25][26]. We show that the upregulation of the AKT/S6 signaling axis is the major pathway conferring OSCC cells radioresistance, and inhibiting it significantly reverses the radioresistance in OSCC cells.…”

Section: Discussionmentioning

confidence: 87%

Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib

Lang

Lam

Chen

et al. 2020

Cells

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Background: Development of radioresistance in oral squamous cell carcinoma (OSCC) remains a significant problem in cancer treatment, contributing to the lack of improvement in survival trends in recent decades. Effective strategies to overcome radioresistance are necessary to improve the therapeutic outcomes of radiotherapy in OSCC patients. Methods: Cells and xenograft tumors were irradiated using the Small Animal Radiation Research Platform. AKT inhibitor capivasertib (AZD5363) was encapsulated into cathepsin B-responsible nanoparticles (NPs) for tumor-specific delivery. Cell viability was measured by alamarBlue, cell growth was determined by colony formation and 3D culture, and apoptosis was assessed by flow cytometry with the staining of Fluorescein isothiocyanate (FITC) Annexin V and PI. An orthotopic tongue tumor model was used to evaluate the in vivo therapeutic effects. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. Results: We show that upregulation of AKT signaling is the critical mechanism for radioresistance in OSCC cells, and AKT inactivation by a selective and potent AKT inhibitor capivasertib results in radiosensitivity. Moreover, relative to irradiation (IR) alone, IR combined with the delivery of capivasertib in association with tumor-seeking NPs greatly enhanced tumor cell repression in 3D cell cultures and OSCC tumor shrinkage in an orthotopic mouse model. Conclusions: These data indicate that capivasertib is a potent agent that sensitizes radioresistant OSCC cells to IR and is a promising strategy to overcome failure of radiotherapy in OSCC patients.

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Section: Discussionmentioning

confidence: 87%

Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib

Lang

Lam

Chen

et al. 2020

Cells

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“…Akt/NF-kb signaling pathway is a common signal transduction pathway in eukaryotic cells. It is involved in cell polarity, cell division, proliferation and apoptosis, cell adhesion and migration, and so on (12,13). Related studies confi rmed that the inhibition of TGF-beta upstream protein can effectively inhibit the collagen gel contraction induced by TGFand the expression of type I collagen (14,15).…”

Section: Discussionmentioning

confidence: 99%

The significance of Akt/NF-κb signaling pathway in the posterior cataract animal model

Shao¹,

Zhu²,

Huo³

et al. 2017

BLL

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OBJECTIVE: To establish SD rat posterior capsular opacifi cation (posterior capsular opacifi cation-PCO) animal model, and to detect the expression of Akt/NF-kb signaling pathway in the PCO model. METHODS: 30 healthy SD rats were randomly divided into control group (0d) and the experimental groups (7d and 14 d), there were 10 rats at all time points. All rats (right eye) were treated with the lens capsule, and the infl ammatory reaction of the anterior segment of the eye and the occurrence of PCO at different time points were observed under the microscope. The TGF-β concentration of humor aquosus was measured at the different time points by ELISA method. Eyeballs were removed after the rats were killed. RT-PCR method was used to detect the gene expression levels of Akt and NF-κb and Westen Blot method to detect the protein expression of Akt, p-Akt, NF-κb and p-NF-κb. RESULTS: TGF-β concentration, Akt and NF-κb gene expression, and Akt, p-Akt, NF-κb and p-NF-κb protein expression in humor aquosus, increased with the time and the time-dependence was signifi cant. CONCLUSION: Akt/NF-κb signaling pathway may be closely related to the occurrence and development of PCO, which may be related to the role of protein phosphorylation (Fig. 5, Ref. 20). Text in PDF www.elis.sk.

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“…As overexpression of ErbB was frequently observed in EScc, ErbB may activate the hedgehog and NF-κB pathways to promote EScc progression. A study in refractory acute myeloid leukemia cells reported that inhibition of smoothened homolog, a transducer of the hedgehog pathway, was accompanied by a decrease in the expression of nuclear NF-κB p65 (36). Inhibition of Gli1 by an inhibitor additionally resulted in inactivation of the NF-κB pathway by reducing the phosphorylation levels of NF-κB p65 in TE-8 cells.…”

Section: Discussionmentioning

confidence: 99%

Interplay between the NF‑κB and hedgehog signaling pathways predicts prognosis in esophageal squamous cell carcinoma following neoadjuvant chemoradiotherapy

et al. 2018

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Tumor recurrence and metastasis in esophageal squamous cell carcinoma (ESCC) are primary causes of patient mortality. The nuclear factor (NF)‑κB signaling pathway and hedgehog signaling pathway were previously reported to contribute to cell growth and metastasis in ESCC. The present study therefore investigated the roles of the NF‑κB and hedgehog pathways in ESCC tumors following neoadjuvant chemoradiotherapy (NCRT). By immunohistochemistry staining, it was observed that NF‑κB and glioma‑associated oncogene homolog 1 (Gli1), key components of the NF‑κB and hedgehog pathways, respectively, were decreased following NCRT, which was further confirmed by western blotting and reverse transcription‑quantitative polymerase chain reaction analysis. In addition, survival analysis suggested that high expression levels of either NF‑κB or Gli1 were associated with poor overall survival (OS) of patients. In the esophageal cell line TE‑8, NF‑κB and Gli1 formed a positive feedback loop, and inhibition of either NF‑κB or Gli1 may inhibit cell migration, invasion and proliferation. The results of the present study demonstrated that activation of the NF‑κB and hedgehog signaling pathways limited the OS of patients with ESCC following NCRT, and may therefore be suitable targets for ESCC treatment.

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Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells

Cited by 61 publications

References 43 publications

Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib

Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib

The significance of Akt/NF-κb signaling pathway in the posterior cataract animal model

Interplay between the NF‑κB and hedgehog signaling pathways predicts prognosis in esophageal squamous cell carcinoma following neoadjuvant chemoradiotherapy

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