Abstract
Human solid tumors contain hypoxic regions that have considerably lower oxygen tension than the normal tissues. Hypoxia offers resistance to radiotherapy and anticancer chemotherapy, as well as predispose to increased tumor metastases. Furthermore, hypoxia induces hypoxia-inducible factor-1 (HIF-1), which in turn increases tumor angiogenesis. Thus, eradication of HIF-1-active/hypoxic tumor cells is very important for cancer therapy. We have previously reported that procaspase-3 fused with a von Hippel–Lindau (VHL)-mediated protein destruction motif of alpha subunit of HIF-1 (HIF-1α) containing Pro564, named TAT-ODD-procaspase-3 (TOP3), specifically induced cell death to hypoxic cells in vivo as well as in vitro. We now report that TOP3 also eradicates the radiation-induced HIF-1-active tumor cells. HIF-1 activity in the xenografts of human tumor cells, which express luciferase under the transcriptional control of HIF-1, were monitored and quantified daily with an in vivo bioluminescence photon-counting device. HIF-1 activity in tumors was more rapidly increased by ionizing radiation (IR) compared to untreated tumors. TOP3 efficiently decreased the HIF-1-activity in irradiated tumors as well as unirradiated ones, indicating TOP3 eradicated tumor cells with HIF-1-activity induced by IR as well as hypoxia. Eradication of HIF-1-active/hypoxic cells in the xenografts during irradiation exhibited significant suppression in angiogenesis and strong enhancement in a long-term growth suppression of tumor xenografts. These results further strengthen the argument that HIF-1-active/hypoxic cells play crucial roles in angiogenesis and radioresistance.
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Abbreviations
- HIF-1:
-
hypoxia-inducible factor-1
- PTD:
-
protein-transduction domain
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Acknowledgements
We are grateful to Dr Ohtsura Niwa for extensive discussion; Akiyo Morinibu, Emi Nishimoto and Naoko Harada for skilled technical assistance. This work was supported in part by grant-in-aid for Scientific Research on Priority Areas, Cancer, from the Ministry of Education, Culture, Sports, Science and Technology, and by a grant-in-aid for the second- and third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare, Japan. This study is a part of joint research, which is focusing on the development of the basis of technology for establishing COE for nano-medicine, carried out through Kyoto City Collaboration of Regional Entities for Advancing Technology Excellence (CREATE) assigned by Japan Science and Technology Agency (JST).
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Harada, H., Kizaka-Kondoh, S., Li, G. et al. Significance of HIF-1-active cells in angiogenesis and radioresistance. Oncogene 26, 7508–7516 (2007). https://doi.org/10.1038/sj.onc.1210556
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DOI: https://doi.org/10.1038/sj.onc.1210556
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