HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs

Tao Zhao, Yuxi Zhu, Akiyo Morinibu, Minoru Kobayashi, Kazumi Shinomiya, Satoshi Itasaka, Michio Yoshimura, Guozheng Guo, Masahiro Hiraoka, Hiroshi Harada

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Abstract

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.

Original languageEnglish (US)
Article number3793
JournalScientific reports
Volume4
DOIs
StatePublished - Jan 23 2014

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Hypoxia-Inducible Factor 1
Reactive Oxygen Species
Lung Neoplasms
Neoplasms
Lung
Pyruvate Dehydrogenase (Lipoamide)
Neoplasm Metastasis
Oxidative Phosphorylation
Glycolysis
Metabolic Networks and Pathways
Fermentation
Lactic Acid
Phosphorylation
Glucose

ASJC Scopus subject areas

  • General

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HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs. / Zhao, Tao; Zhu, Yuxi; Morinibu, Akiyo; Kobayashi, Minoru; Shinomiya, Kazumi; Itasaka, Satoshi; Yoshimura, Michio; Guo, Guozheng; Hiraoka, Masahiro; Harada, Hiroshi.

In: Scientific reports, Vol. 4, 3793, 23.01.2014.

Research output: Contribution to journalArticle

Zhao, T, Zhu, Y, Morinibu, A, Kobayashi, M, Shinomiya, K, Itasaka, S, Yoshimura, M, Guo, G, Hiraoka, M & Harada, H 2014, 'HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs', Scientific reports, vol. 4, 3793. https://doi.org/10.1038/srep03793
Zhao, Tao ; Zhu, Yuxi ; Morinibu, Akiyo ; Kobayashi, Minoru ; Shinomiya, Kazumi ; Itasaka, Satoshi ; Yoshimura, Michio ; Guo, Guozheng ; Hiraoka, Masahiro ; Harada, Hiroshi. / HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs. In: Scientific reports. 2014 ; Vol. 4.
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AU - Shinomiya, Kazumi

AU - Itasaka, Satoshi

AU - Yoshimura, Michio

AU - Guo, Guozheng

AU - Hiraoka, Masahiro

AU - Harada, Hiroshi

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