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dc.contributor.authorLinn, Douglas Ernest
dc.date.accessioned2011-06-14T19:05:33Z
dc.date.available2011-06-14T19:05:33Z
dc.date.issued2011
dc.identifier.urihttp://hdl.handle.net/10713/521
dc.descriptionUniversity of Maryland, Baltimore. Toxicology. Ph.D. 2011en_US
dc.description.abstractThe standard of care for patients with advanced prostate cancer is hormone ablation, a treatment that is often initially effective, but eventually fails. Second line therapy options are limited and patients frequently acquire resistance to the chemotherapeutic drugs used. Pim-1 kinases have previously been described as diagnostic biomarkers for prostate cancer progression and serve roles in chemoresistance. Here we investigated the role of Pim-1 kinases during advanced prostate cancer progression focusing on how they may promote resistance and subsequent failure of both hormone ablation and chemotherapy approaches. The androgen receptor (AR) has a central role in castration resistance, a stage where many prostate cancer patients exhibit recurrent tumor growth even under androgen ablation. Our studies demonstrate that Pim-1 kinases can regulate AR activity in different ways. The 33 kDa isoform Pim-1S induces AR degradation, a process which has been previously shown to be a critical process for cell cycle progression of prostate cancer cells. The 44 kDa isoform Pim-1L stabilizes AR levels thereby enhancing AR-mediated transcription and expression of downstream target genes. Both Pim-1 kinase isoforms were able to promote prostate cancer cell growth under androgen depleted conditions, which is a potential contributing factor that may lead to castration resistance. Characterization of drug-resistant prostate cancer cell lines revealed that Pim-1L and pluripotency transcription factor OCT4 were upregulated. We observed transcriptionally active OCT4 was critical for the enhanced tumorigenicity of these resistant lines, as knock-down by short hairpin RNA dramatically decreased in vitro and in vivo tumor growth. Pim-1 target sites T235/S236 were found to be essential for target gene expression and transcriptional activity. Together these experiments suggested Pim-1 kinases could promote maintenance of an aggressive tumor-initiating cell population through OCT4 signaling and provided yet another mechanism by which Pim-1 kinases could facilitate therapeutic failure. In summary, we have provided evidence that Pim-1 kinases can promote resistance to prostate cancer therapy by two interrelated mechanisms. Our data suggest that targeting Pim-1 kinases may prove valuable in preventing therapy resistance or for resensitizing patients to chemotherapeutic drugs currently used for treatment.en_US
dc.language.isoen_USen_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectchemoresistanceen_US
dc.subjectkinaseen_US
dc.subjectOCT4en_US
dc.subjectPim-1en_US
dc.subject.lcshProstate--Canceren_US
dc.subject.meshReceptors, Androgenen_US
dc.titleThe role of Pim-1 kinases in advanced prostate cancer therapeutic resistanceen_US
dc.typedissertationen_US
dc.contributor.advisorQiu, Yun


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