Limd1 Radiosensitizes Human Non-Small Cell Lung Cancer Cells Via Inhibiting Nf-Kb Signaling

INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS(2015)

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摘要
Radiation therapy achieved remarkable effects in the treatment of non-small cell lung cancer (NSCLC). However, to identify bio-makers that could predict or enhance radiosensitivity to improve outcomes of NSCLC patients remains urgent. LIMD1 was shown to be downregulated in NSCLC and plays pivotal roles in NSCLC development. However, whether LIMD1 was a potential target for enhancing radiosensitivity and the underling mechanisms remains unknown. This study aims at demonstrating LIMD1 to be a target for enhancing radiosensitivity and uncovering the underling mechanisms. Clonogenic assay was performed to analyze the effects of LIMD1 on radiosensitivity of NSCLC cells. FACS and immunofluorescence assays were applied to detect cell apoptosis and autophagic cell death. Luciferase reporter analysis, gene set enrichment analysis, Western blotting, qRT-PCR and Co-IP were applied to demonstrate that LIMD1 modulating NF-κB signaling. In the current study, we found that LIMD1 was significantly downregulated in NSCLC, and its expression positively correlated with radiosensitivity of NSCLC cells. Ectopic overexpression of LIMD1 radiosensitized NSCLC cells by increasing apoptosis and autophagic cell death, while knockdown LIMD1 led to radiation resistance. Further investigation revealed that LIMD1 bound p65 to inhibit NF-κB signaling to downregulating Bcl-2, Bcl-xL, which plays pivotal roles in blocking apoptosis and autophagy, and subsequently enhancing radiosensitivity of NSCLC cells. In summary, this study proved that LIMD impaired NF-κB/ Bcl-2, Bcl-xL signaling via binding p65 directly or indirectly, leading to increased cell apoptosis and autophagic cell death and further enhancing radiosensitivity of NSCLC cells. This study suggested that LIMD1could be used as a novel radiosensitivity predictor and a promising therapeutic target for NSCLC.
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Cancer Biomarkers
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