12486-12491 Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter

Anne Le, Zachary E. Stine, Christopher Nguyen, Junaid Afzal, Peng Sun, Max Hamaker, Nicholas M. Siegel, Arvin M. Gouw, Byung Hak Kang, Shu Han Yu, Rory L. Cochran, Kurt A. Sailor, Hongjun Song, Chi V. Dang

Research output: Contribution to journalArticlepeer-review

Abstract

Although aerobic glycolysis provides an advantage in the hypoxic tumor microenvironment, some cancer cells can also respire via oxidative phosphorylation. These respiring ("non-Warburg") cells were previously thought not to play a key role in tumorigenesis and thus fell from favor in the literature. We sought to determine whether subpopulations of hypoxic cancer cells have different metabolic phenotypes and gene-expression profiles that could influence tumorigenicity and therapeutic response, and we therefore developed a dual fluorescent protein reporter, HypoxCR, that detects hypoxic [hypoxia-inducible factor (HIF) active] and/or cycling cells. Using HEK293T cells as a model, we identified four distinct hypoxic cell populations by flow cytometry. The non-HIF/noncycling cell population expressed a unique set of genes involved in mitochondrial function. Relative to the other subpopulations, these hypoxic "non-Warburg" cells had highest oxygen consumption rates and mitochondrial capacity consistent with increased mitochondrial respiration. We found that these respiring cells were unexpectedly tumorigenic, suggesting that continued respiration under limiting oxygen conditions may be required for tumorigenicity.

Original languageEnglish (US)
Pages (from-to)12486-12491
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number34
DOIs
StatePublished - Aug 26 2014

Keywords

  • Antiangiogenesis
  • Metabolism
  • Mitochondria

ASJC Scopus subject areas

  • General

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