SDH5 depletion enhances radiosensitivity by regulating p53: A new method for noninvasive prediction of radiotherapy response

Yan Zong, Qianwen Li, Furong Zhang, Xunde Xian, Sihua Wang, Jiahong Xia, Jie Li, Zhan Tuo, Guangqin Xiao, Li Liu, Guiling Li, Sheng Zhang, Gang Wu, Jun Liu

Research output: Contribution to journalArticle

Abstract

Radiotherapy is an effective treatment for lung cancer but lacks a reliable prediction method. Cell-free nucleic acids in plasma have been reported as a novel tumor marker. Here, we evaluate circulating succinate dehydrogenase 5 (SDH5) mRNA in plasma and SDH5 protein in tumors, assess their predictive value in lung cancer patients undergoing radiotherapy, and explore the underlying mechanisms. Methods: SDH5 expression was measured in peripheral blood samples and fresh tumor specimens from 208 non-small cell lung cancer (NSCLC) patients and correlated with clinical outcomes. SDH5 knockout mice and human xenograft mice were used to evaluate radiosensitivity. Cell growth, apoptosis, and the DNA damage response were assessed. Relevant RNA and protein levels were analyzed by qRT-PCR and Western blotting. Immunoprecipitation and GST pulldown assays were performed to detect protein-protein interactions. Polyubiquitination of p53 was examined by an in vitro ubiquitination assay. Results: Plasma and tumor SDH5 mRNA levels were positively correlated (rho=0.894, P<0.001). Patients with relatively low SDH5 levels in plasma (0.47, 0.12-0.89) and tumors (3.85, 0.96-7.23) had a better prognosis after radiotherapy (median PFS: 30.0 versus 15.0 months, hazard ratio: 0.276, 95% CI: 0.201–0.379, P<0.001). In SDH5 knockout mice, the lung epithelial cells exhibited increased DNA damage after radiation. In human lung xenograft mice, SDH5-deficient tumors had a smaller volume after radiotherapy. Furthermore, SDH5 depletion inhibits p53 degradation via the ubiquitin/proteasome pathway, which promotes apoptosis and enhances radiosensitivity in NSCLC. Conclusion: Our findings provide a novel noninvasive method for prediction of response to radiotherapy and may have significant implications for cancer radiotherapy.

Original languageEnglish (US)
Pages (from-to)6380-6395
Number of pages16
JournalTheranostics
Volume9
Issue number22
DOIs
StatePublished - Jan 1 2019

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Succinate Dehydrogenase
Radiation Tolerance
Radiotherapy
Neoplasms
Heterografts
Knockout Mice
Non-Small Cell Lung Carcinoma
DNA Damage
Lung Neoplasms
Proteins
Apoptosis
Lung
Messenger RNA
Ubiquitination
Proteasome Endopeptidase Complex
Tumor Biomarkers
Ubiquitin
Immunoprecipitation
Nucleic Acids
Western Blotting

Keywords

  • Apoptosis
  • Lung cancer
  • Noninvasive
  • P53
  • Prediction
  • Radiotherapy
  • SDH5

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

Cite this

SDH5 depletion enhances radiosensitivity by regulating p53 : A new method for noninvasive prediction of radiotherapy response. / Zong, Yan; Li, Qianwen; Zhang, Furong; Xian, Xunde; Wang, Sihua; Xia, Jiahong; Li, Jie; Tuo, Zhan; Xiao, Guangqin; Liu, Li; Li, Guiling; Zhang, Sheng; Wu, Gang; Liu, Jun.

In: Theranostics, Vol. 9, No. 22, 01.01.2019, p. 6380-6395.

Research output: Contribution to journalArticle

Zong, Y, Li, Q, Zhang, F, Xian, X, Wang, S, Xia, J, Li, J, Tuo, Z, Xiao, G, Liu, L, Li, G, Zhang, S, Wu, G & Liu, J 2019, 'SDH5 depletion enhances radiosensitivity by regulating p53: A new method for noninvasive prediction of radiotherapy response', Theranostics, vol. 9, no. 22, pp. 6380-6395. https://doi.org/10.7150/thno.34443
Zong, Yan ; Li, Qianwen ; Zhang, Furong ; Xian, Xunde ; Wang, Sihua ; Xia, Jiahong ; Li, Jie ; Tuo, Zhan ; Xiao, Guangqin ; Liu, Li ; Li, Guiling ; Zhang, Sheng ; Wu, Gang ; Liu, Jun. / SDH5 depletion enhances radiosensitivity by regulating p53 : A new method for noninvasive prediction of radiotherapy response. In: Theranostics. 2019 ; Vol. 9, No. 22. pp. 6380-6395.
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abstract = "Radiotherapy is an effective treatment for lung cancer but lacks a reliable prediction method. Cell-free nucleic acids in plasma have been reported as a novel tumor marker. Here, we evaluate circulating succinate dehydrogenase 5 (SDH5) mRNA in plasma and SDH5 protein in tumors, assess their predictive value in lung cancer patients undergoing radiotherapy, and explore the underlying mechanisms. Methods: SDH5 expression was measured in peripheral blood samples and fresh tumor specimens from 208 non-small cell lung cancer (NSCLC) patients and correlated with clinical outcomes. SDH5 knockout mice and human xenograft mice were used to evaluate radiosensitivity. Cell growth, apoptosis, and the DNA damage response were assessed. Relevant RNA and protein levels were analyzed by qRT-PCR and Western blotting. Immunoprecipitation and GST pulldown assays were performed to detect protein-protein interactions. Polyubiquitination of p53 was examined by an in vitro ubiquitination assay. Results: Plasma and tumor SDH5 mRNA levels were positively correlated (rho=0.894, P<0.001). Patients with relatively low SDH5 levels in plasma (0.47, 0.12-0.89) and tumors (3.85, 0.96-7.23) had a better prognosis after radiotherapy (median PFS: 30.0 versus 15.0 months, hazard ratio: 0.276, 95{\%} CI: 0.201–0.379, P<0.001). In SDH5 knockout mice, the lung epithelial cells exhibited increased DNA damage after radiation. In human lung xenograft mice, SDH5-deficient tumors had a smaller volume after radiotherapy. Furthermore, SDH5 depletion inhibits p53 degradation via the ubiquitin/proteasome pathway, which promotes apoptosis and enhances radiosensitivity in NSCLC. Conclusion: Our findings provide a novel noninvasive method for prediction of response to radiotherapy and may have significant implications for cancer radiotherapy.",
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AU - Li, Qianwen

AU - Zhang, Furong

AU - Xian, Xunde

AU - Wang, Sihua

AU - Xia, Jiahong

AU - Li, Jie

AU - Tuo, Zhan

AU - Xiao, Guangqin

AU - Liu, Li

AU - Li, Guiling

AU - Zhang, Sheng

AU - Wu, Gang

AU - Liu, Jun

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AB - Radiotherapy is an effective treatment for lung cancer but lacks a reliable prediction method. Cell-free nucleic acids in plasma have been reported as a novel tumor marker. Here, we evaluate circulating succinate dehydrogenase 5 (SDH5) mRNA in plasma and SDH5 protein in tumors, assess their predictive value in lung cancer patients undergoing radiotherapy, and explore the underlying mechanisms. Methods: SDH5 expression was measured in peripheral blood samples and fresh tumor specimens from 208 non-small cell lung cancer (NSCLC) patients and correlated with clinical outcomes. SDH5 knockout mice and human xenograft mice were used to evaluate radiosensitivity. Cell growth, apoptosis, and the DNA damage response were assessed. Relevant RNA and protein levels were analyzed by qRT-PCR and Western blotting. Immunoprecipitation and GST pulldown assays were performed to detect protein-protein interactions. Polyubiquitination of p53 was examined by an in vitro ubiquitination assay. Results: Plasma and tumor SDH5 mRNA levels were positively correlated (rho=0.894, P<0.001). Patients with relatively low SDH5 levels in plasma (0.47, 0.12-0.89) and tumors (3.85, 0.96-7.23) had a better prognosis after radiotherapy (median PFS: 30.0 versus 15.0 months, hazard ratio: 0.276, 95% CI: 0.201–0.379, P<0.001). In SDH5 knockout mice, the lung epithelial cells exhibited increased DNA damage after radiation. In human lung xenograft mice, SDH5-deficient tumors had a smaller volume after radiotherapy. Furthermore, SDH5 depletion inhibits p53 degradation via the ubiquitin/proteasome pathway, which promotes apoptosis and enhances radiosensitivity in NSCLC. Conclusion: Our findings provide a novel noninvasive method for prediction of response to radiotherapy and may have significant implications for cancer radiotherapy.

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