Endostatin Sensitizes p53-Deficient Non-Small Cell Lung Cancer to Genotoxic Chemotherapy by Targeting DNA-PKcs

Abstract

Endostatin was discovered as an endogenous angiogenesis inhibitor with broad-spectrum antitumor activities. Although clinical efficacy was observed when combining endostatin 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 identified that endostatin exerts a direct chemosensitizing effect on p53-deficient tumor 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-PKcs in tumor cells and suppresses its DNA repair activity. Using isogenic NSCLC cells with different p53 status, we discovered that p53-deficient tumor cells exhibit chemo-resistance 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 accumulated DNA lesions and promoting the therapeutic effect of genotoxic chemotherapy. On the contrary, p53-proficient tumor 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 of 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 tumors.

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