Extracellular signal-regulated kinase 5 increases radioresistance of lung cancer cells by enhancing the DNA damage response

Jiang, Weiwei; Jin, Guang‐Hui; Cai, Fangfang; Chen, Xiao; Cao, Nini; Zhang, Xiangyu; Liu, Jia; Chen, Fei; Wang, Rui; Dong, Wei; Zhuang, Hongqin; Zhang, Hua

doi:10.1038/s12276-019-0209-3

Cited by 35 publications

(34 citation statements)

References 51 publications

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“…It has also been reported that ERK5 could regulate tobacco smoke-induced pulmonary, hepatic and urocystic EMT in vivo and in vitro (Geng et al, 2015;Liang et al, 2015a;Liang et al, 2015b;Liang et al, 2017;Min et al, 2017). Our team previously reported that ERK5 could increase the radioresistance of lung cancer cells by enhancing DNA damage responses (Jiang et al, 2019).…”

Section: Research Articlementioning

confidence: 83%

Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner

Jiang

Cai

et al. 2020

Protein Cell

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This study was designed to evaluate ERK5 expression in lung cancer and malignant melanoma progression and to ascertain the involvement of ERK5 signaling in lung cancer and melanoma. We show that ERK5 expression is abundant in human lung cancer samples, and elevated ERK5 expression in lung cancer was linked to the acquisition of increased metastatic and invasive potential. Importantly, we observed a significant correlation between ERK5 activity and FAK expression and its phosphorylation at the Ser 910 site. Mechanistically, ERK5 increased the expression of the transcription factor USF1, which could transcriptionally upregulate FAK expression, resulting in FAK signaling activation to promote cell migration. We also provided evidence that the phosphorylation of FAK at Ser 910 was due to ERK5 but not ERK1/2, and we then suggested a role for Ser 910 in the control of cell motility. In addition, ERK5 had targets in addition to FAK that regulate epithelial-to-mesenchymal transition and cell motility in cancer cells. Taken together, our findings uncover a cancer metastasis-promoting role for ERK5 and provide the rationale for targeting ERK5 as a potential therapeutic approach.

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Section: Research Articlementioning

confidence: 83%

Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner

Jiang

Cai

et al. 2020

Protein Cell

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“…G2/M checkpoint can repair DNA damage and induce apoptosis upon being unrepaired. Accumulating evidence has confirmed that cell cycle arrest may result in radiosensitivity [28][29][30]. Cell cycle checkpoints are rapidly activated through a p53-dependent mechanism in normal cells.…”

Section: Discussionmentioning

confidence: 99%

Riluzole Enhances the Response of Human Nasopharyngeal Carcinoma Cells to Ionizing Radiation via ATM/P53 Signalling Pathway

Sun

Jun

et al. 2020

J. Cancer

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Riluzole is approved by the FDA as an amyotrophic lateral sclerosis (ALS) drug. Previous studies showed that treatment with riluzole suppressed the proliferation of many cancer cells. However, little is known about its effects on nasopharyngeal carcinoma (NPC) and its molecular mode of action. In this study, we determined the effect of riluzole on apoptosis, cell cycle, migration, and invasion in NPC cell lines and investigated its mechanism at the molecular level. By using the human NPC cell lines CNE1, CNE2, and HNE1, we revealed that riluzole effectively inhibited viability of the NPC cell lines in dose-and time-dependent manners. Furthermore, riluzole dose-dependently induced apoptosis and G2/M cell cycle arrest in the NPC cell lines. After combination with radiotherapy (RT), greater cytotoxicity was achieved than with riluzole or RT alone in vitro and vivo. This was associated with the activation of ataxia telangiectasia mutated (ATM) and phosphoinositide p53 pathways. P53 silencing reduced cell reactiveness to riluzole therapy. These observations demonstrate that the riluzole-activated ATM/P53 pathway is directly involved in radiation-induced apoptosis of NPC cells. Given the acceptable side effect, combining of riluzole and radiotherapy is promising in NPC treatment.

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“…NSCLC cells were seeded into 6-well plates at a density of 1,000 cells per well and cultured for 4 hr for initial attachment. Subsequently, the cells were treated with 50 μm of quercetin (Sigma, St. Louis, MO) for 24 hr, followed by irradiation at specified doses (2,4,6,or 8 Gy) given at 2 Gy/min (RS-2000 Biological irradiator, Rad Source Technologies). Then, the cells were cultured for 2 weeks at 37 C in 5% CO 2 before the medium was discarded and the cells were washed twice with PBS.…”

Section: Colony Formation Assaymentioning

confidence: 99%

“…During radiotherapy, ionizing radiation rays destroy the DNA of tumor cells, thereby suppressing their proliferation and inducing their apoptosis . Unfortunately, multiple factors lead to radiation resistance in tumor cells, while the increase in the radiation dose will also increase the risk of radiotherapy‐related complications, such as radiation pneumonitis and radiation pulmonary fibrosis . Therefore, it is urgent to develop drugs that can enhance the radiosensitivity of NSCLC cells to improve the efficacy of radiotherapy.…”

Section: Introductionmentioning

confidence: 99%

Quercetin radiosensitizes non‐small cell lung cancer cells through the regulation of miR‐16‐5p/WEE1 axis

et al. 2020

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Background Quercetin, a widely distributed bioflavonoid, plays a role in combating diverse human cancers including non‐small cell lung cancer (NSCLC). However, the role of quercetin in reversing the radioresistance of NSCLC cells and its underlying mechanism are far from being elucidated. Method Radiation‐resistant NSCLC cell lines were established. Quantitative real‐time PCR (qRT‐PCR) was used to detect the expression of miR‐16‐5p and WEE1 G2 checkpoint kinase (WEE1) mRNA in radiation‐resistant cells. After being treated with different concentrations of quercetin and different doses of X‐ray, cell proliferation and apoptosis were monitored by CCK‐8 assay, colony formation assay, and flow cytometry, respectively. Ultimately, the targeting relationship between miR‐16‐5p and WEE1 was verified via a dual fluorescent reporter gene assay. Results The expression of miR‐16‐5p was down‐regulated in radiation‐resistant cells, while the expression of WEE1 was up‐regulated. Quercetin enhanced the radiosensitivity of NSCLC cells in a dose‐ and time‐dependent manner. Furthermore, quercetin treatment increased the expression of miR‐16‐5p and decreased the expression of WEE1. The function of quercetin was reversed by miR‐16‐5p inhibitors or the transfection of WEE1 overexpressing plasmids. Conclusion In conclusion, quercetin enhanced the radiosensitivity of NSCLC cells via modulating the expression of miR‐16‐5p and WEE1.

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Extracellular signal-regulated kinase 5 increases radioresistance of lung cancer cells by enhancing the DNA damage response

Cited by 35 publications

References 51 publications

Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner

Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner

Riluzole Enhances the Response of Human Nasopharyngeal Carcinoma Cells to Ionizing Radiation via ATM/P53 Signalling Pathway

Quercetin radiosensitizes non‐small cell lung cancer cells through the regulation of miR‐16‐5p/WEE1 axis

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