Golgi Phosphoprotein 3 Confers Radioresistance via Stabilizing EGFR in Lung Adenocarcinoma.

Autor:	Chen G; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, PR China., Kong P; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, PR China., Yang M; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, PR China; University of Science and Technology of China, Hefei, PR China; Clinical Pathology Center, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, PR China., Hu W; School of Basic Medical Science, Anhui Medical University, Hefei, PR China., Prise KM; Centre for Cancer Research & Cell Biology, Queen's University Belfast, Belfast, United Kingdom., Yu KN; Department of Physics, City University of Hong Kong, Hong Kong, PR China; State Key Laboratory in Marine Pollution, City University of Hong Kong, Hong Kong, PR China., Cui S; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, PR China; University of Science and Technology of China, Hefei, PR China., Qin F; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, PR China; University of Science and Technology of China, Hefei, PR China., Meng G; Clinical Pathology Center, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, PR China; Department of Pathology, Anhui Medical University, Hefei, PR China., Almahi WA; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, PR China; University of Science and Technology of China, Hefei, PR China., Nie L; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, PR China., Han W; Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, PR China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Suzhou, PR China. Electronic address: hanw@hfcas.ac.cn.
Jazyk:	angličtina
Zdroj:	International journal of radiation oncology, biology, physics [Int J Radiat Oncol Biol Phys] 2022 Apr 01; Vol. 112 (5), pp. 1216-1228. Date of Electronic Publication: 2021 Nov 26.
DOI:	10.1016/j.ijrobp.2021.11.023
Abstrakt:	Purpose: 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. Methods and Materials: 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. Results: 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. Conclusions: 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. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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