Impaired OXPHOS Complex III in Breast Cancer

Owens, Kjerstin M.; Kulawiec, Mariola; Desouki, Mohamad Mokhtar; Vanniarajan, Ayyasamy; Singh, Keshav K.

doi:10.1371/journal.pone.0023846

Cited by 90 publications

(87 citation statements)

References 34 publications

(49 reference statements)

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“…Although the mitochondria of ovarian cancer cells are known to be competent (18), little is known regarding the differences in metabolism between ovarian cancer cells of different invasive potential and in nonadherent conditions. In contrast to previously known results for adherent cells (3,25), we found that OCR was significantly higher in nonadherent conditions in the more invasive ovarian cell line SKOV3ip1 than the less invasive cell line OVCAR3 ( Fig. 2A).…”

Section: Increase In Ocr In Highly Invasive Ovarian Cancer Cells In Dcontrasting

confidence: 99%

Pyruvate uptake is increased in highly invasive ovarian cancer cells under anoikis conditions for anaplerosis, mitochondrial function, and migration

Caneba

Bellancé

Yang

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Anoikis resistance, or the ability for cells to live detached from the extracellular matrix, is a property of epithelial cancers. The "Warburg effect," or the preference of cancer cells for glycolysis for their energy production even in the presence of oxygen, has been shown to be evident in various tumors. Since a cancer cell's metastatic ability depends on microenvironmental conditions (nutrients, stromal cells, and vascularization) and is highly variable for different organs, their cellular metabolic fluxes and nutrient demand may show considerable differences. Moreover, a cancer cell's metastatic ability, which is dependent on the stage of cancer, may further create metabolic alterations depending on its microenvironment. Although recent studies have aimed to elucidate cancer cell metabolism under detached conditions, the nutrient demand and metabolic activity of cancer cells under nonadherent conditions remain poorly understood. Additionally, less is known about metabolic alterations in ovarian cancer cells with varying invasive capability under anoikis conditions. We hypothesized that the metabolism of highly invasive ovarian cancer cells in detachment would differ from less invasive ovarian cancer cells and that ovarian cancer cells will have altered metabolism in detached vs. attached conditions. To assess these metabolic differences, we integrated a secretomics-based metabolic footprinting (MFP) approach with mitochondrial bioenergetics. Interestingly, MFP revealed higher pyruvate uptake and oxygen consumption in more invasive ovarian cancer cells than their less invasive counterparts. Furthermore, ATP production was higher in more invasive vs. less invasive ovarian cancer cells in detachment. We found that pyruvate has an effect on highly invasive ovarian cancer cells' migration ability. Our results are the first to demonstrate that higher mitochondrial activity is related to higher ovarian cancer invasiveness under detached conditions. Importantly, our results bring insights regarding the metabolism of cancer cells under nonadherent conditions and could lead to the development of therapies for modulating cancer cell invasiveness. oxidative phosphorylation; metabolomics; Warburg effect; bioenergetics; cancer migration and anoikis OVARIAN CANCER REMAINS A LEADING CAUSE of gynecological malignancy-related deaths and is often detected in the late stages, when the cancer has already metastasized (5). Of all ovarian cancer diagnoses, most are classified as epithelial ovarian carcinoma (17). In the process of epithelial ovarian cancer metastasis, cancer cells can remain viable while they are suspended in peritoneal fluid in the peritoneal cavity. A normal epithelial cell would in this environment undergo anoikis or epithelial cell death due to detachment, first coined by Frisch and Francis (8) in 1994. However, cancer cells, including ovarian cancer cells, can survive without extracellular matrix attachment and are thus considered anoikis resistant. Anoikis resistance in cancer has been widely studied from t...

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Section: Increase In Ocr In Highly Invasive Ovarian Cancer Cells In Dcontrasting

confidence: 99%

Pyruvate uptake is increased in highly invasive ovarian cancer cells under anoikis conditions for anaplerosis, mitochondrial function, and migration

Caneba

Bellancé

Yang

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…In a series of 31 renal carcinomas, complex II activities are 6-fold lower than in controls [34]. Complex II activity was found decreased in breast cancer cell lines [29].…”

Section: Complex IImentioning

confidence: 84%

“…For instance, the OXPHOS enzyme activities and protein levels are not uniformly decreased in breast cancer cell lines. The spectrum of decrease is MCF7 (complexes II, III, and V), T47D (complexes I, III), SKBr3 (complexes III, IV, and V), and MDA-MB-231 (complexes I, III, IV, and V) [29]. Interestingly, the most aggressive breast cancer line (MDA-MB-231) displays the broadest OXPHOS defect.…”

Section: Oxidative Phosphorylation Markersmentioning

confidence: 99%

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Mitochondrial Markers for Cancer: Relevance to Diagnosis, Therapy, and Prognosis and General Understanding of Malignant Disease Mechanisms

Paepe

2012

ISRN Pathology

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Cancer cells display changes that aid them to escape from cell death, sustain their proliferative powers, and shift their metabolism toward glycolytic energy production. Mitochondria are key organelles in many metabolic and biosynthetic pathways, and the adaptation of mitochondrial function has been recognized as crucial to the changes that occur in cancer cells. This paper zooms in on the pathologic evaluation of mitochondrial markers for diagnosing and staging of human cancer and determining the patients’ prognoses.

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“…This protein has been associated with oncogene-induced senescence and found to be upregulated in breast cancer cells and primary breast tumours (Owens et al, 2011).…”

Section: Mitochondrial Functionmentioning

confidence: 99%

The growth hormone receptor mediated oncogenesis

Chhabra¹

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Growth hormone (GH) is a major regulator of postnatal growth, cellular proliferation and differentiation, as well as of metabolism. All actions of GH are mediated via its cognate Growth Hormone Receptor (GHR). It is now clear that the role of GH extends well beyond the conventional notions of longitudinal growth and childhood development. A substantial body of evidence supports a role for the GH/IGF-1 axis in cancer incidence and progression in animals and humans and because of widespread clinical application of GH, there has been considerable interest in the mechanism of activation of its receptor. It was originally thought that GH initiated its actions by sequentially binding two GHR monomers, resulting in receptor dimerisation and initiation of intracellular signalling cascades, including Jak/STAT and MAPK pathways. However, recent evidence by our group and others has indicated that the GHR is constitutively dimerised, and that dimerisation alone is not sufficient for GHR activation.To this end the main objective of this thesis was to evaluate the role of GH-mediated signalling via its GHR in mediating oncogenesis. We have taken a multi-disciplinary approach by first determining how the GHR is activated via its transmembrane domain (TMD) and the nature of its interaction with Src family of tyrosine kinase (Lyn). We have determined the basis of the contrasting actions of autocrine GH from independent publications and sought to evaluate the effect of various constitutively active GHR constructs in cancer promotion in vitro and in vivo by establishing a tissue-specific delivery system (TVA system) for introducing multiple genes in a spatial and temporally controlled manner. We have provided the molecular basis of increased cancer susceptibility of the first reported GHR variant from two independent epidemiological studies. Finally, we have evaluated cancer resistance and anti-aging pathways in various GHR knockin and knockout mice models.In order to determine the role of GHR transmembrane domain (TMD) and upper juxtamembrane domain (JMD) in signalling, cysteine-scanning mutagenesis was employed with truncated and full length receptors in a thiol-free background. Using these GHR constructs and sequentially substituting residues along the GHR JMD and TMD with cysteine we observed a ligandindependent spontaneous dimerisation pattern of upper JMD and TMD residues with evidence for a 'tilt and twist' movement for this region of GHR during activation. By using Cu-o-phenanthroline we were able to show that GHR activation could occur following disulfide bond formation at the upper TMD boundary resulting in constitutive activation. Finally we were able to conclude that GHR activation requires the JMD residues to come in close proximity which results in separation of iii the lower TMD residues and activation. Another outcome of this study was the generation of the first full-length constitutively active receptor.GHR has been shown to activate numerous pathways and one such pathway involves Src Family Kinase (SFK),...

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Impaired OXPHOS Complex III in Breast Cancer

Cited by 90 publications

References 34 publications

Pyruvate uptake is increased in highly invasive ovarian cancer cells under anoikis conditions for anaplerosis, mitochondrial function, and migration

Pyruvate uptake is increased in highly invasive ovarian cancer cells under anoikis conditions for anaplerosis, mitochondrial function, and migration

Mitochondrial Markers for Cancer: Relevance to Diagnosis, Therapy, and Prognosis and General Understanding of Malignant Disease Mechanisms

The growth hormone receptor mediated oncogenesis

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