Fenofibrate Increases Radiosensitivity in Head and Neck Squamous Cell Carcinoma via Inducing G2/M Arrest and Apoptosis

Liu, Jia; Ge, Yangyang; Zhu, Hongcheng; Yang, Xi; Cai, Jing; Zhang, Chi; Lu, Junyan; Li, Zhan; Qin, Qin; Yang, Yan; Yu, Yan; Zhang, Hao; Chen, Xiaochen; Liu, Zheming; Ma, Jianxin; Cheng, Hongyan; Sun, Xinchen

doi:10.7314/apjcp.2014.15.16.6649

Cited by 16 publications

(11 citation statements)

References 30 publications

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“…A large number of studies have found that cell cycle regulation has a significant impact on the survival of tumor cells and their sensitivity to radiotherapy, where G2/M phase arrest can enhance the sensitivity of tumor cells to radiotherapy (17)(18)(19). The present study found that after radiotherapy, the G2/M phase ratio of HSC-4 cells in the experimental group was not significantly different compared with that in the control groups.…”

Section: Discussioncontrasting

confidence: 53%

Silencing of FANCD2 enhances the radiosensitivity of metastatic cervical lymph node-derived head and neck squamous cell carcinoma HSC-4 cells

Feng

Bao

Zeng

et al. 2017

International Journal of Oncology

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Abstract. Fanconi anemia complementation group D2 (FANCD2) is involved in the key steps of the Fanconi anemia (FA) pathway, which plays a role in the repair of DNA crosslink damage. However, the role of FANCD2 during radiotherapy for head and neck squamous cell carcinoma (HNSCC) is unclear. In this study, the HNSCC cell line HSC-4 was used. Western blotting was used to evaluate the expression of the FANCD2 in HSC-4 cells. We investigated the impact of FANCD2 on the radiosensitivity of HSC-4 cells in vitro and in vivo. TUNEL, western blotting and immunohistochemistry were used to analyze the apoptosis and proteins involved in apoptosisrelated pathways after radiotherapy to investigate the relevant mechanism. The present study showed that shRNA interference could effectively and stably silence FANCD2 expression in HSC-4 cells. In vitro, the silencing of FANCD2 inhibited cell proliferation, decreased the survival rate, increased apoptosis and induced S phase arrest in HSC-4 cells after radiotherapy. In vivo, the silencing of FANCD2 could prolong the tumor-forming time and slow tumor growth. In addition, the tumor volume was significantly reduced, the weight was deceased, and the tumor inhibition rate was increased after radiotherapy. TUNEL showed that the silencing of FANCD2 significantly increased apoptosis in HSC-4 cells induced by radiotherapy. Both in vitro and in vivo esperiments revealed that the expression of the Bax and p-p38 proteins in HSC-4 cells, in which FANCD2 had been silenced, was increased after radiotherapy, whereas the expression of the p38 and Bcl2 proteins was decreased. Our results suggested that the silencing of FANCD2 enhanced the radiosensitivity of HSC-4 cells, and its mechanism involves the activation of the p38 MAPK signaling pathway and the regulation of the expression of Bax and Bcl2 proteins. This study provides a novel candidate target for HNSCC therapy.

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Section: Discussioncontrasting

confidence: 53%

Silencing of FANCD2 enhances the radiosensitivity of metastatic cervical lymph node-derived head and neck squamous cell carcinoma HSC-4 cells

Feng

Bao

Zeng

et al. 2017

International Journal of Oncology

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“…The induction of cell cycle arrest at the G2/M phase in tumor cells may be an effective strategy for enhancing the ionizing radiation effect against tumors [28]. Numerous recent studies have shown that increasing radiation-induced G2/M phase arrest in tumor cells can significantly increase the sensitivity of HNSCC, cervical cancer, and prostate cancer cells to ionizing radiation[29][30][31][32]. In the present study, the cell cycle detection results after irradiation showed that the proportion of cells in the G2/M phase in the CNE-2sh group was significantly higher than that in the control group cells, indicating that FANCD2 silencing significantly increased radiation-induced G2/M phase cell cycle arrest in the CNE-2 cells and enhanced their ionizing radiation sensitivity.Interestingly, in ionizing radiation sensitivity experiments involving bone marrow stromal cells and IL-3-dependent hematopoietic stem cells of FANCD2-deficient mice, Berhane et al found that the growth life of bone marrow stromal cells was shortened and showed strong radiation sensitivity and DNA damage involvement.…”

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confidence: 99%

FANCD2 knockdown with shRNA interference enhances the ionizing radiation sensitivity of nasopharyngeal carcinoma CNE-2 cells

Bao

Feng

Zhao

et al. 2021

neo

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Fanconi anemia complementation group D2 (FANCD2) has been associated with the sensitivity of tumor cells to DNA crosslinking damaging agents in certain solid tumors. However, its role in nasopharyngeal carcinoma (NPC) is still unclear. In the present study, the role of FANCD2 in the response of NPC CNE-2 cells to radiation was investigated. A CNE-2 cell model with stable FANCD2 silencing was constructed by lentiviral transfection. Fluorescence quantitative PCR and western blotting were used to evaluate FANCD2 expression in CNE-2 cells. The biological impact of FANCD2 silencing on the response of CNE-2 cells to radiation was investigated in vitro and in vivo. The microarray technology, western blotting, and immunohistochemistry were used to analyze the proteins involved in related pathways after irradiation to investigate the underlying mechanism. Lentivirus-mediated shRNA interference stably silenced the FANCD2 gene in CNE-2 cells. In vitro, in the FANCD2-silenced group, cell proliferation was significantly inhibited, apoptosis was increased, and the cell cycle was arrested at the G2/M phase after irradiation. In vivo, FANCD2 s ilencing slowed tumor growth, as the volume and weight of the xenograft tumors were significantly decreased. Both in vitro and in vivo, the differentially expressed genes NUPR1, FLI1, and FGF21 were downregulated in the FANCD2-silenced group. Our results show that FANCD2 silencing affected the sensitivity of CNE-2 cells to ionizing radiation by regulating cell proliferation, apoptosis, and cell cycle distribution. The mechanism might be associated with changes in NUPR1, FLI1, and FGF21 protein expression due to the FANCD2 silencing. This study provides a promising target for NPC radiotherapy.

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“…For example, fenofibrate inhibited G 1 /S phase progression in endometrial cancer by down-regulation of Cyclin D1 (CCND1) 23 , and in glioblastoma cells by activation of FoxO3A/Bim apoptotic axis 25 . In head and neck squamous cell carcinoma, fenofibrate leaded to G 2 /M arrest via reducing the activity of the CDK1/cyclinB1 kinase complex 26 . To elucidate the anti-tumor mechanism of bezafibrate, we virtual screened out some bezafibrate-binding candidate proteins by TarFisDock (Table 2 ).…”

Section: Discussionmentioning

confidence: 99%

Expression Profiling Identifies Bezafibrate as Potential Therapeutic Drug for Lung Adenocarcinoma

Li¹,

Yang²,

Chen³

et al. 2015

J. Cancer

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Drug-induced gene expression patterns that invert disease profiles have recently been illustrated to be a new strategy for drug-repositioning. In the present study, we validated this approach and focused on prediction of novel drugs for lung adenocarcinoma (AC), for which there is a pressing need to find novel therapeutic compounds. Firstly, connectivity map (CMap) analysis computationally predicted bezafibrate as a putative compound against lung AC. Then this hypothesis was verified by in vitro assays of anti-proliferation and cell cycle arrest. In silico docking evidence indicated that bezafibrate could target cyclin dependent kinase 2(CDK2), which regulates progression through the cell cycle. Furthermore, we found that bezafibrate can significantly down-regulate the expression of CDK2 mRNA and p-CDK2. Using a nude mice xenograft model, we also found that bezafibrate could inhibit tumor growth of lung AC in vivo. In conclusion, this study proposed bezafibrate as a potential therapeutic option for lung AC patients, illustrating the potential of in silico drug screening.

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Fenofibrate Increases Radiosensitivity in Head and Neck Squamous Cell Carcinoma via Inducing G2/M Arrest and Apoptosis

Cited by 16 publications

References 30 publications

Silencing of FANCD2 enhances the radiosensitivity of metastatic cervical lymph node-derived head and neck squamous cell carcinoma HSC-4 cells

Silencing of FANCD2 enhances the radiosensitivity of metastatic cervical lymph node-derived head and neck squamous cell carcinoma HSC-4 cells

FANCD2 knockdown with shRNA interference enhances the ionizing radiation sensitivity of nasopharyngeal carcinoma CNE-2 cells

Expression Profiling Identifies Bezafibrate as Potential Therapeutic Drug for Lung Adenocarcinoma

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