title: Mitochondrial deficiency impairs hypoxic induction of HIF-1 transcriptional activity and retards tumor growth.
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.
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.|Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Koido
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Haga
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Furuno
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Tsukahara
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Sakurai
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Tani
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Sato
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.|Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomida
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D019073:HT29 Cells; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: D004272:DNA, Mitochondrial; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: HIF-1; HIF-1α; hypoxia; mitochondria; ρ0