HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs.
Hypoxia-inducible factor 1 (HIF-1) has been associated with distant tumor metastasis; however, its function in multiple metastatic processes has not yet been fully elucidated. In the present study, we demonstrated that cancer cells transiently upregulated HIF-1 activity during their metastatic colonization after extravasation in the lungs in hypoxia-independent and reactive oxygen species (ROS)-dependent manners. Transient activation induced the expression of lactate dehydrogenase A and phosphorylation of the E1α subunit of pyruvate dehydrogenase, which indicated the reprogramming of glucose metabolic pathways from mitochondrial oxidative phosphorylation to anaerobic glycolysis and lactic acid fermentation. The administration of the HIF-1 inhibitor, YC-1, inhibited this reprogramming, increased intratumoral ROS levels, and eventually suppressed the formation of metastatic lung tumors. These results indicate that HIF-1-mediated metabolic reprogramming is responsible for the survival of metastatic cancers during their colonization in lungs by reducing cytotoxic ROS levels; therefore, its blockade by HIF-1-inhibitors is a rational strategy to prevent tumor metastasis.
1] Group of Radiation and Tumor Biology, Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine. 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University. Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] Department of Radiation Medicine, Fourth Military Medical University. 17 Changle West Road, Xi'an, Shaanxi 710032, China.
Tao
T
Zhao
1] Group of Radiation and Tumor Biology, Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine. 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University. Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] Department of Oncology, The First Affiliated Hospital of Chongqing Medical University. No.1 Friendship Road, Yuanjiagang, Yuzhong District, Chongqing 400016, China.
Yuxi
Y
Zhu
1] Group of Radiation and Tumor Biology, Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine. 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University. Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Akiyo
A
Morinibu
1] Group of Radiation and Tumor Biology, Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine. 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University. Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Minoru
M
Kobayashi
1] Group of Radiation and Tumor Biology, Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine. 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University. Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Kazumi
K
Shinomiya
Group of Radiation and Tumor Biology, Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine. 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Satoshi
S
Itasaka
Group of Radiation and Tumor Biology, Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine. 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Michio
M
Yoshimura
Department of Radiation Medicine, Fourth Military Medical University. 17 Changle West Road, Xi'an, Shaanxi 710032, China.
Guozheng
G
Guo
Group of Radiation and Tumor Biology, Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine. 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Masahiro
M
Hiraoka
1] Group of Radiation and Tumor Biology, Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine. 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan [2] Group of Radiation and Tumor Biology, Career-Path Promotion Unit for Young Life Scientists, Kyoto University. Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Hiroshi
H
Harada
D000693:Anaerobiosis; D000818:Animals; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D019344:Lactic Acid / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
D051793:Hypoxia-Inducible Factor 1; D017382:Reactive Oxygen Species; D019344:Lactic Acid; D005947:Glucose