4.7 Article

Endostatin sensitizes p53-deficient non-small-cell lung cancer to genotoxic chemotherapy by targeting DNA-dependent protein kinase catalytic subunit

期刊

JOURNAL OF PATHOLOGY
卷 243, 期 2, 页码 255-266

出版社

WILEY
DOI: 10.1002/path.4952

关键词

NSCLC; endostatin; p53; DNA-PKcs; chemotherapy

资金

  1. General Programmes of the National Natural Science Foundation of China [81672865, 81472667, 81461148021, 81272529]
  2. Major Scientific and Technological Special Project [2013ZX09509103]

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Endostatin was discovered as an endogenous angiogenesis inhibitor with broad-spectrum antitumour activities. Although clinical efficacy was observed when endostatin was combined with standard chemotherapy for non-small cell lung cancer (NSCLC), as well as other cancer types, the specific mechanisms underlying the benefit of endostatin are not completely understood. Extensive investigations suggest that endostatin is a multifunctional protein possessing more than anti-angiogenic activity. Here, we found that endostatin exerts a direct chemosensitizing effect on p53-deficient tumour cells. Concomitant treatment with endostatin and genotoxic drugs resulted in therapeutic synergy in both cellular and animal models of p53-deficient NSCLC. Mechanistically, endostatin specifically interacts with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in tumour cells and suppresses its DNA repair activity. Using isogenic NSCLC cells with different p53 statuses, we discovered that p53-deficient tumour cells show chemoresistance to genotoxic drugs, creating a synthetic dependence on DNA-PKcs-mediated DNA repair. In this setting, endostatin exerted inhibitory effects on DNA-PKcs activity, leading to accumulation of DNA lesions and promotion of the therapeutic effect of genotoxic chemotherapy. In contrast, p53-proficient tumour cells were more sensitive to genotoxic drugs so that DNA-PKcs could be cleaved by drug-activated caspase-3, making DNA-PKcs inhibition less effective during this ongoing apoptotic process. Therefore, our data demonstrate a novel mechanism for endostatin as a DNA-PKcs suppressor, and indicate that combination therapy of endostatin with genotoxic drugs could be a promising treatment strategy for cancer patients with p53-deficient tumours. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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