Every year in the US, over 200,000 men are diagnosed with prostate cancer (PCa) and annual mortality in the US exceeds 30,000. PCa is treated surgically, and post-surgical recurrent tumors treated through targeted inhibition of the androgen receptor (AR) and AR signaling through disruption of androgen synthesis. If tumors resist antiandrogen therapy, castration recurrent (CR) tumors are treated with second line therapies that currently involve more potent inhibition of AR. Since the advent of these newer therapies, alternative, AR-independent resistance mechanisms have begun to become more prevalent. Thus, there is a need to explore and discover novel pathways, drug targets, and mechanisms driving aggressive and atypical subtypes of PCa.
Non-coding RNAs (ncRNAs) are known to play critical roles in normal cell behavior, as well as various diseases including cancer. Small nucleolar RNAs (snoRNAs) are one class of ncRNAs that are primarily involved in guiding specific enzymatic modifications (e.g. 2’O-methylation, pseudouridylation) of ribosomal RNAs (rRNAs) and thereby allowing fidelity of ribosome biogenesis. HBII-52 is an orphan C/D box snoRNA encoded in tandem repeat copies at chromosomal locus 15q11-13. HBII-52 has no predicted or reported rRNA targets, however, it has both predicted and validated messenger RNA (mRNA) targets, including the serotonin 2c receptor (5-HT2cR, encoded by the gene HTR2C). 5-HT2cR is a G-Protein Coupled Receptor (GPCR) predominantly expressed in brain, and it controls appetite and signaling via cognate ligand, serotonin (5-HT) binding. The pre-mRNA encoding 5-HT2cR is subject to complex alternative processing including alternative pre-mRNA splicing and Adenosine-to-Inosine (A-to-I) RNA editing. HBII-52 promotes processing to, highly active isoforms of 5-HT2cR, thus potentiating its signaling axis. A variety of inhibitors of 5-HT2cR exist including potent and selective inhibitors like SB242,084 that have already undergone preclinical evaluation for neurologic disorders.
Herein, we report that the expression levels of HBII-52 (MBII-52 in mouse) and 5-HT2cR are deregulated in PCa including both mouse and human preclinical models, and human clinical specimens. Furthermore, mechanistic studies of the HBII-52/5-HT2cR pathway in PCa cells indicated this pathway drives transition to an aggressive and invasive phenotype, specifically by a highly active, less edited isoform of 5-HT2cR. Finally, we evaluated the feasibility and efficacy of targeting 5-HT2cR using small molecules in PCa and arrived at a lead drug candidate, SB242,084. In conclusion, active edit-isoforms of 5-HT2cR promote aggressiveness and invasiveness of PCa cells. One potential mode of activation includes upregulation of HBII-52. HBII-52/5-HT2cR-positive cancer cells can be effectively targeted through selective inhibition of 5-HT2cR with small molecules.
|Advisor:||Foster, Barbara A.|
|Commitee:||Das, Gokul M., Goodrich, David W., Higgins, Michael J.|
|School:||State University of New York at Buffalo|
|Department:||Roswell Park . Pharmacology|
|School Location:||United States -- New York|
|Source:||DAI-B 77/02(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Pharmacology|
|Keywords:||Drug target, Prostate cancer, RNA editing, Serotonin 2C receptor, snoRNA|
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