The role of Pim-1 kinases in advanced prostate cancer therapeutic resistance
Abstract
The 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.Description
University of Maryland, Baltimore. Toxicology. Ph.D. 2011Identifier to cite or link to this item
http://hdl.handle.net/10713/521The following license files are associated with this item:
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