Study of insulin-like growth factor signaling in mitochondrial function

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dc.contributor.advisor O'Connor, Rosemary en
dc.contributor.author Lyons, Amy
dc.date.accessioned 2016-09-07T10:16:13Z
dc.date.issued 2016
dc.date.submitted 2016
dc.identifier.citation Lyons, A. 2016. Study of insulin-like growth factor signaling in mitochondrial function. PhD Thesis, University College Cork. en
dc.identifier.uri http://hdl.handle.net/10468/3070
dc.description.abstract Insulin-like Growth Factor-1 (IGF-1) signalling promotes cell growth and is associated with cancer progression, including metastasis, epithelial-mesenchymal transition (EMT), and resistance to therapy. Mitochondria play an essential role in cancer cell metabolism and accumulating evidence demonstrates that dysfunctional mitochondria associated with release of mitochondrial reactive oxygen species (ROS) can influence cancer cell phenotype and invasive potential. We previously isolated a mitochondrial UTP carrier (PNC1/SLC25A33) whose expression is regulated by IGF-1, and which is essential for mitochondrial maintenance. PNC1 suppression in cancer cells results in mitochondrial dysfunction and acquisition of a profound ROS-dependent invasive (EMT) phenotype. Moreover, over-expression of PNC1 in cancer cells that exhibit an EMT phenotype is sufficient to suppress mitochondrial ROS production and reverse the invasive phenotype. This led us to investigate the IGF-1-mitochondrial signalling axis in cancer cells. We found that IGF-1 signalling supports increased mitochondrial mass and Oxphos potential through a PI3K dependant pathway. Acute inhibition of IGF-1R activity with a tyrosine kinase inhibitor results in dysfunctional mitochondria and cell death. We also observed an adaptive response to IGF-1R inhibition upon prolonged exposure to the kinase inhibitor, where increased expression of the EGF receptor can compensate for loss of mitochondrial mass through activation of PI3K/mTOR signalling. However, these cells exhibit impaired mitochondrial biogenesis and mitophagy. We conclude that the IGF-1 is required for mitochondrial maintenance and biogenesis in cancer cells, and that pharmacological inhibition of this pathway may induce mitochondrial dysfunction and may render the cells more sensitive to glycolysis-targeted drugs. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2016, Amy Lyons. en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject IGF-1R en
dc.subject Mitochondria en
dc.subject Biogenesis en
dc.subject Mitophagy en
dc.subject Therapy resistance en
dc.title Study of insulin-like growth factor signaling in mitochondrial function en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Science) en
dc.internal.availability Full text not available en
dc.check.info Indefinite en
dc.check.date 10000-01-01
dc.description.version Accepted Version
dc.description.status Not peer reviewed en
dc.internal.school Biochemistry en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Yes en
dc.thesis.opt-out true
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat Both hard copy thesis and e-thesis en
dc.internal.conferring Autumn 2016 en


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© 2016, Amy Lyons. Except where otherwise noted, this item's license is described as © 2016, Amy Lyons.
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