Oncotarget

Research Papers:

Mitochondrial deficiency impairs hypoxic induction of HIF-1 transcriptional activity and retards tumor growth

Masaru Koido _, Naomi Haga, Aki Furuno, Satomi Tsukahara, Junko Sakurai, Yuri Tani, Shigeo Sato and Akihiro Tomida

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Oncotarget. 2017; 8:11841-11854. https://doi.org/10.18632/oncotarget.14415

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Abstract

Masaru Koido1,2, Naomi Haga1, Aki Furuno1, Satomi Tsukahara1, Junko Sakurai1, Yuri Tani1, Shigeo Sato1, Akihiro Tomida1,2

1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan

2Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

Correspondence to:

Akihiro Tomida, email: [email protected]

Keywords: HIF-1, HIF-1α, hypoxia, ρ0, mitochondria

Received: April 24, 2016     Accepted: December 16, 2016     Published: January 02, 2017

ABSTRACT

Mitochondria can be involved in regulating cellular stress response to hypoxia and tumor growth, but little is known about that mechanistic relationship. Here, we show that mitochondrial deficiency severely retards tumor xenograft growth with impairing hypoxic induction of HIF-1 transcriptional activity. Using mtDNA-deficient ρ0 cells, we found that HIF-1 pathway activation was comparable in slow-growing ρ0 xenografts and rapid-growing parental xenografts. Interestingly, we found that ex vivo ρ0 cells derived from ρ0 xenografts exhibited slightly increased HIF-1α expression and modest HIF-1 pathway activation regardless of oxygen concentration. Surprisingly, ρ0 cells, as well as parental cells treated with oxidative phosphorylation inhibitors, were unable to boost HIF-1 transcriptional activity during hypoxia, although HIF-1α protein levels were ordinarily increased in these cells under hypoxic conditions. These findings indicate that mitochondrial deficiency causes loss of hypoxia-induced HIF-1 transcriptional activity and thereby might lead to a constitutive HIF-1 pathway activation as a cellular adaptation mechanism in tumor microenvironment.


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PII: 14415