Mitochondrial bioenergetics of metastatic breast cancer cells in response to dynamic changes in oxygen tension: effects of HIF-1α

Solid tumors are characterized by regions of low oxygen tension (OT), which play a central role in tumor progression and resistance to therapy. Low OT affects mitochondrial function and for the cells to survive, mitochondria must functionally adapt to low OT to maintain the cellular bioenergetics. I...

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Published in:PloS one 2013-06, Vol.8 (6), p.e68348-e68348
Main Authors: Diers, Anne R, Vayalil, Praveen K, Oliva, Claudia R, Griguer, Corinne E, Darley-Usmar, Victor, Hurst, Douglas R, Welch, Danny R, Landar, Aimee
Format: Article
Language:English
Subjects:
Acidification
Adaptation
Adaptation, Biological - genetics
Adaptation, Biological - physiology
Bioenergetics
Biology
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - physiopathology
Cancer
Cardiomyocytes
Cell Line, Tumor
Cell Respiration - genetics
Cell Respiration - physiology
Chemical compounds
Electron transport
Energy Metabolism - genetics
Energy Metabolism - physiology
Female
Free radicals
Gene expression
Glucose - metabolism
Glycolysis - genetics
Glycolysis - physiology
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Kinases
Medicine
Metabolism
Metastases
Metastasis
Mitochondria
Mitochondria - genetics
Mitochondria - metabolism
Mitochondria - pathology
Mitochondria - physiology
Neoplasm Metastasis - genetics
Neoplasm Metastasis - physiopathology
Oxygen
Oxygen - metabolism
Oxygen consumption
Oxygen Consumption - genetics
Oxygen Consumption - physiology
Oxygen tension
Pathology
Pharmacology
Respiration
Rodents
Solid tumors
Tension
Tumors
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Landar, Aimee
description Solid tumors are characterized by regions of low oxygen tension (OT), which play a central role in tumor progression and resistance to therapy. Low OT affects mitochondrial function and for the cells to survive, mitochondria must functionally adapt to low OT to maintain the cellular bioenergetics. In this study, a novel experimental approach was developed to examine the real-time bioenergetic changes in breast cancer cells (BCCs) during adaptation to OT (from 20% to
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Low OT affects mitochondrial function and for the cells to survive, mitochondria must functionally adapt to low OT to maintain the cellular bioenergetics. In this study, a novel experimental approach was developed to examine the real-time bioenergetic changes in breast cancer cells (BCCs) during adaptation to OT (from 20% to &lt;1% oxygen) using sensitive extracellular flux technology. Oxygen was gradually removed from the medium, and the bioenergetics of metastatic BCCs (MDA-MB-231 and MCF10CA clones) was compared with non-tumorigenic (MCF10A) cells. BCCs, but not MCF10A, rapidly responded to low OT by stabilizing HIF-1α and increasing HIF-1α responsive gene expression and glucose uptake. BCCs also increased extracellular acidification rate (ECAR), which was markedly lower in MCF10A. Interestingly, BCCs exhibited a biphasic response in basal respiration as the OT was reduced from 20% to &lt;1%. The initial stimulation of oxygen consumption is found to be due to increased mitochondrial respiration. This effect was HIF-1α-dependent, as silencing HIF-1α abolished the biphasic response. During hypoxia and reoxygenation, BCCs also maintained oxygen consumption rates at specific OT; however, HIF-1α silenced BCC were less responsive to changes in OT. Our results suggest that HIF-1α provides a high degree of bioenergetic flexibility under different OT which may confer an adaptive advantage for BCC survival in the tumor microenvironment and during invasion and metastasis. This study thus provides direct evidence for the cross-talk between HIF-1α and mitochondria during adaptation to low OT by BCCs and may be useful in identifying novel therapeutic agents that target the bioenergetics of BCCs in response to low OT.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23840849</pmid><doi>10.1371/journal.pone.0068348</doi><oa>free_for_read</oa></addata></record>
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subjects Acidification
Adaptation
Adaptation, Biological - genetics
Adaptation, Biological - physiology
Bioenergetics
Biology
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - physiopathology
Cancer
Cardiomyocytes
Cell Line, Tumor
Cell Respiration - genetics
Cell Respiration - physiology
Chemical compounds
Electron transport
Energy Metabolism - genetics
Energy Metabolism - physiology
Female
Free radicals
Gene expression
Glucose - metabolism
Glycolysis - genetics
Glycolysis - physiology
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Kinases
Medicine
Metabolism
Metastases
Metastasis
Mitochondria
Mitochondria - genetics
Mitochondria - metabolism
Mitochondria - pathology
Mitochondria - physiology
Neoplasm Metastasis - genetics
Neoplasm Metastasis - physiopathology
Oxygen
Oxygen - metabolism
Oxygen consumption
Oxygen Consumption - genetics
Oxygen Consumption - physiology
Oxygen tension
Pathology
Pharmacology
Respiration
Rodents
Solid tumors
Tension
Tumors
title Mitochondrial bioenergetics of metastatic breast cancer cells in response to dynamic changes in oxygen tension: effects of HIF-1α
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