Golgi Phosphoprotein 3 Confers Radioresistance via Stabilizing EGFR in Lung Adenocarcinoma
| Autor: | Wanglai Hu, K.N. Yu, Feng Qin, Kevin M. Prise, Gang Meng, Wei Han, Waleed Abdelbagi Almahi, Lili Nie, Shujun Cui, Miaomiao Yang, Guodong Chen, Peizhong Kong |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Lung Neoplasms DNA Repair DNA damage Adenocarcinoma of Lung Apoptosis Radiation Tolerance SDG 3 - Good Health and Well-being Radioresistance Cell Line Tumor medicine Humans Radiology Nuclear Medicine and imaging Epidermal growth factor receptor Clonogenic assay Gene knockdown Radiation biology business.industry Cancer Membrane Proteins DNA medicine.disease Phosphoproteins ErbB Receptors Oncology Cancer research biology.protein Adenocarcinoma business |
| Zdroj: | Chen, G, Kong, P, Yang, M, Hu, W, Prise, K M, Yu, K N, Cui, S, Qin, F, Meng, G, Almahi, W A, Nie, L & Han, W 2021, ' Golgi Phosphoprotein 3 Confers Radioresistance via Stabilizing EGFR in Lung Adenocarcinoma ', International journal of radiation oncology, biology, physics . https://doi.org/10.1016/j.ijrobp.2021.11.023 |
| ISSN: | 1879-355X |
| DOI: | 10.1016/j.ijrobp.2021.11.023 |
| Popis: | Radioresistance is a major cause of treatment failure in tumor radiation therapy, and the underlying mechanisms of radioresistance are still elusive. Golgi phosphoprotein 3 (GOLPH3) has been reported to associate tightly with cancer progression and chemoresistance. Herein, we explored whether GOLPH3 mediated radioresistance of lung adenocarcinoma (LUAD) and whether targeted suppression of GOLPH3 sensitized LUAD to radiation therapy.The aberrant expression of GOLPH3 was evaluated by immunohistochemistry in LUAD clinical samples. To evaluate the association between GOLPH3 and radioresistance, colony formation and apoptosis were assessed in control and GOLPH3 knockdown cells. γ-H2AX foci and level determination and micronucleus test were used to analyze DNA damage production and repair. The rescue of GOLPH3 knockdown was then performed by exogenous expression of small interfering RNA-resistant mutant GOLPH3 to confirm the role of GOLPH3 in DNA damage repair. Mechanistically, the effect of GOLPH3 on regulating stability and nuclear accumulation of epidermal growth factor receptor (EGFR) and the activation of DNA-dependent protein kinase (DNA-PK) were investigated by quantitative real-time polymerase chain reaction, western blot, immunofluorescence, and coimmunoprecipitation. The role of GOLPH3 in vivo in radioresistance was determined in a xenograft model.In tumor tissues of 33 patients with LUAD, the expression of GOLPH3 showed significant increases compared with those in matched normal tissues. Knocking down GOLPH3 reduced the clonogenic capacity, impaired double-strand break (DSB) repair, and enhanced apoptosis after irradiation. In contrast, reversal of GOLPH3 depletion rescued the impaired repair of radiation-induced DSBs. Mechanistically, loss of GOLPH3 accelerated the degradation of EGFR in lysosome, causing the reduction in EGFR levels, thereby weakening nuclear accumulation of EGFR and attenuating the activation of DNA-PK. Furthermore, adenovirus-mediated GOLPH3 knockdown could enhance the ionizing radiation response in the LUAD xenograft model.GOLPH3 conferred resistance of LUAD to ionizing radiation via stabilizing EGFR, and targeted suppression of GOLPH3 might be considered as a potential therapeutic strategy for sensitizing LUAD to radiation therapy. |
| Databáze: | OpenAIRE |
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