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dc.contributor.supervisor Gibson, Spencer (Biochemistry and Medical Genetics) en
dc.contributor.author Azad, Meghan Brianne
dc.date.accessioned 2010-09-10T17:55:03Z
dc.date.available 2010-09-10T17:55:03Z
dc.date.issued 2010-09-10T17:55:03Z
dc.identifier.citation Azad MB, Chen Y, Henson ES, Cizeau J, McMillan-Ward E, Israels SJ, Gibson SB. Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy. 2008 Feb 16; 4(2):195-204. en
dc.identifier.citation Azad MB, Chen Y, Gibson SB. Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment. Antioxid Redox Signal. 2009 Apr; 11(4):777-90. en
dc.identifier.uri http://hdl.handle.net/1993/4137
dc.description.abstract INTRODUCTION: Autophagy is a regulated degradation pathway functioning in both cell survival and cell death. Its role in cancer is controversial since autophagy can be protective or destructive to tumor cells, depending on individual genetic signatures, stage of malignancy and treatment conditions. Hypoxia is a common feature of solid tumors, correlating with poor prognosis and chemoresistance. We have investigated autophagy in hypoxic cancer cells and examined the role of the hypoxia-inducible protein, BNIP3. METHODS: Multiple cancer cell lines were exposed to chronic hypoxia (<1% O2) in the presence or absence of specific inhibitors for autophagy and apoptosis. Cell death was measured by membrane permeability assay, and autophagy was assayed by GFP-LC3 distribution, LC3 processing, electron microscopy, and acidic vacuole formation. BNIP3 was over-expressed by transient transfection, stably induced in a tetracycline-regulated expression system, or knocked down using siRNA. Whole brain morphology, cell proliferation, and hypoxic response were additionally studied in a BNIP3-null mouse model. RESULTS: Autophagic cell death was detected in hypoxic cancer cells, occurring independent of apoptosis through a mechanism involving BNIP3. BNIP3 itself induced autophagic cell death, and loss of BNIP3 protected against hypoxia-induced autophagy and cell death. Loss of BNIP3 also resulted in differential growth and cell cycle progression in vitro, and increased brain cellularity in vivo compared to wild type controls. Potential mediators of resistance to BNIP3-induced cell death were identified using a novel model of BNIP3 resistance. CONCLUSIONS: Taken together, these results support the emerging theory that autophagy represents an alternative cell death pathway that could be targeted in hypoxic and/or apoptosis-resistant tumors. We have specifically identified BNIP3 as a potential target molecule in this pathway. Finally, we have identified a possibly novel role for BNIP3 in brain development and cell cycle regulation. These findings have important clinical applications given the potential for personalized cancer therapy based on individual tumor characteristics including autophagic capacity, hypoxic status, and BNIP3 activity. en
dc.format.extent 4324684 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.rights info:eu-repo/semantics/openAccess
dc.subject hypoxia en
dc.subject cancer en
dc.subject autophagy en
dc.subject BNIP3 en
dc.title The Role of BNIP3 in Proliferation and Hypoxia-Induced Autophagy: Implications for Cancer Therapy en
dc.type info:eu-repo/semantics/doctoralThesis
dc.degree.discipline Biochemistry and Medical Genetics en
dc.contributor.examiningcommittee Murphy, Leigh (Biochemistry and Medical Genetics) Mowat, Michael (Biochemistry and Medical Genetics) Eisenstat, David (Human Anatomy & Cell Science) Hill, Richard (Ontario Cancer Institute / University of Toronto) en
dc.degree.level Doctor of Philosophy (Ph.D.) en
dc.description.note October 2010 en


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