| dc.identifier.uri | http://hdl.handle.net/11401/76513 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Cancer mortality rates remain high and the reason for this lack of progress in improving survival rates is the lack of drugs specifically targeting metastasis, which is the cause of death for 90% of cancer patients. In order to address this important aspect of cancer biology, we used a three-dimensional, high-throughput phenotypic screening approach and a target-based design to identify compounds that interfere with an early, critical stage of the metastatic process, namely cancer cell invasion. By using our phenotypic screening, we identified trifluoperazine (TFP), an FDA approved anti-psychotic, as an anti-invasive agent that interferes with migratory function with minimal cytotoxicity. TFP functions to decrease active, phosphorylated AKT (Thr308 and Ser473) and β -cateninSer552. There is a resultant decrease in β -catenin nuclear translocation and transcription of target genes, based on antibody array data. The activity of TFP on highly invasive fibrosarcoma cells results in decreased angiogenesis and invasion through the basement membrane in a chorioallantoic membrane assay. Overall, we have demonstrated that TFP is responsible for the reduced invasive behavior of these cancer cells by antagonism of a network that includes dopamine receptor D2, AKT, and β -catenin leading to reduced cancer cell motility. Another approach to drug discovery is a target-based approach. Considering the expression of MMP-14 contributes significantly to cancer cell invasion and is correlated with disease progression, MMP-14 is a crucial molecule to target. There are no current inhibitors for this protease and we determined the minimal region of another cell surface molecule, CD44, which is required to interact with MMP-14 for cell migration. We identified an eight amino acid region of CD44 that is crucial for MMP-14 interaction based on mutational analyses. Expression of CD44 with the minimal mutation results in decreased interaction with wild-type MMP-14 based on co-immunoprecipitation assays. Furthermore, MMP-14 mediated cell migration is reduced when co-expressed with the mutant as opposed to wild-type CD44. Furthermore, design of peptides mimicking the minimal region of CD44 reduces interaction of wild-type CD44 and MMP-14 based on a reduction in MMP-14 pulldown by CD44 and reduced MMP-14 mediated migration in the presence of the peptide. Overall, we have identified novel peptides and potential strategies for reduction of metastasis by targeting of cancer cell invasion and migration via target- and phenotype-based screening methods. | |
| dcterms.available | 2017-09-20T16:50:30Z | |
| dcterms.contributor | Sampson, Nicole | en_US |
| dcterms.contributor | Cao, Jian | en_US |
| dcterms.contributor | Tsirka, Styliani-Anna | en_US |
| dcterms.contributor | Zucker, Stanley. | en_US |
| dcterms.creator | Pulkoski-Gross, Ashleigh Elizabeth | |
| dcterms.dateAccepted | 2017-09-20T16:50:30Z | |
| dcterms.dateSubmitted | 2017-09-20T16:50:30Z | |
| dcterms.description | Department of Molecular and Cellular Pharmacology. | en_US |
| dcterms.extent | 105 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/76513 | |
| dcterms.issued | 2015-05-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:50:30Z (GMT). No. of bitstreams: 1
PulkoskiGross_grad.sunysb_0771E_12226.pdf: 2845959 bytes, checksum: 15408ac1aae1a89e9c7d9b3b244ad737 (MD5)
Previous issue date: 2015 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | cancer, CD44, high-throughput screening, metastasis, MMP-14, trifluoperazine | |
| dcterms.subject | Cellular biology | |
| dcterms.title | Cancer Invasion and Metastasis: Unraveling the Mechanism and Developing Novel Therapeutic Agents | |
| dcterms.type | Dissertation | |
