HIF: A Key Survival Factor for Serum-Deprived Prostrate Cancer Cells
dc.contributor.advisor | Jamboor Vishwanatha | |
dc.contributor.committeeMember | Harlan Jones | |
dc.contributor.committeeMember | Raghu Krishnamoorthy | |
dc.creator | Thomas, Rusha | |
dc.date.accessioned | 2019-08-22T20:53:30Z | |
dc.date.available | 2019-08-22T20:53:30Z | |
dc.date.issued | 2008-05-01 | |
dc.date.submitted | 2013-11-15T13:18:03-08:00 | |
dc.description.abstract | Thomas, Rusha, HIF: A key survival factor for serum-deprived prostate cancer cells. Doctor of Philosophy (Molecular Biology and Immunology), May 2008, 134 pages, 47 illustrations, reference list, 105 titles. The hypoxia-inducible factor (HIF) is central to hypoxic adaptation of tumors, and consists of an oxygen-labile HIF-1α and a constitutively expressed HIF-1β subunit. In specific aim 1, we report that prolonged serum deprivation is a potent inducer of HIF-1α in PC-3 and LNCaP prostate cancer (PCa) cells, despite normal oxygen conditions. In contrast, cells grown in the presence of serum did not upregulate HIF-1α protein levels. Moreover, HIF-1α protein increase during serum deprivation correlated with increased cell survival, while suppression of HIF-1α expression significantly decreased PCa cell viability. Our results further demonstrate that HIF-1α protein increase during serum deprivation is due to increased HIF-1α protein synthesis. First, there was no significant increase in HIF-1α mRNA. Secondly, cycloheximide, a protein synthesis inhibitor, prevented HIF-1α protein increase in serum-deprived PCa cells. Moreover, the expression of HIF-1α-target genes, VEGF and IGF-2, was concomitantly increased in serum-deprived PCa cells, while suppression of HIF-1α expression markedly inhibited their induction. Most interestingly, our study showed a significant decline in PCa cell survival following inhibitor of IGF-2 activity. Taken together, our study demonstrates for the first time that PCa cells counteract the stress of prolonged serum deprivation by upregulating HIF-1α protein which increases IGF-2 expression to promote cell survival. In specific aims 2 and 3, we investigated the molecular mechanism of autocrine regulation of HIF-1α, IGF-2 and cell survival in serum-deprived PC-3 and LNCaP PCa cells. We detected a time-dependent increase in Akt activation during serum deprivation, and inhibition of Akt activation attenuated the serum deprivation-mediated increase in HIF-1α and cell survival. Importantly, IGF-2 secretion significantly increased during serum deprivation, and was accompanied by increased activation of its receptor, insulin-like growth factor-I receptor (IGF-IR). Additionally, inhibition of IGF-2 activity markedly suppressed the serum deprivation-mediated increase in IGF-IR and Akt activation, HIF-1α expression, as well as its own transcription, suggesting autocrine regulation of HIF-1α expression via IGF-2. Reciprocal regulation of the IGF-2/IGF-IR system and P13K-Akt pathway was further demonstrated by findings wherein Akt activation was prevented following suppression of IGF-IR expression, and IGF-IR activation was inhibited following P13K inhibition. Lastly, HIF-1α suppression abolished the serum deprivation-mediated increase in Akt activation, and also resulted in higher IGF-IR protein levels indicating reduced IGF-IR activation. Collectively, our study demonstrates that a HIF-1α-dependent autocrine feedback loop upregulates HIF-1α, and thus promotes survival of normoxic, serum-deprived PCa cells. | |
dc.format.mimetype | application/pdf | |
dc.identifier.uri | https://hdl.handle.net/20.500.12503/28880 | |
dc.language.iso | en | |
dc.provenance.legacyDownloads | 0 | |
dc.subject | Cancer Biology | |
dc.subject | Cell and Developmental Biology | |
dc.subject | Cell Biology | |
dc.subject | Cells | |
dc.subject | Cellular and Molecular Physiology | |
dc.subject | Diseases | |
dc.subject | Life Sciences | |
dc.subject | Male Urogenital Diseases | |
dc.subject | Medical Cell Biology | |
dc.subject | Medicine and Health Sciences | |
dc.subject | Other Cell and Developmental Biology | |
dc.subject | Prostate cancer cells | |
dc.subject | hypoxia-inducible factor | |
dc.subject | tumors | |
dc.subject | oxygen-labile HIF-1α | |
dc.subject | LNCaP prostate cnacer cells | |
dc.subject | PCa | |
dc.subject | cycloheximide | |
dc.subject | cell survival | |
dc.subject | P13K inhibition | |
dc.title | HIF: A Key Survival Factor for Serum-Deprived Prostrate Cancer Cells | |
dc.type | Dissertation | |
dc.type.material | text | |
thesis.degree.department | Graduate School of Biomedical Sciences | |
thesis.degree.discipline | Microbiology and Immunology | |
thesis.degree.grantor | University of North Texas Health Science Center at Fort Worth | |
thesis.degree.name | Doctor of Philosophy |
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