The overall survival for neuroblastoma remains dismal, in part due to the emergence of resistance to chemotherapeutic drugs resulting in aggressive, refractory disease. As a neuroendocrine tumor, neuroblastomas secrete a number of peptides; one such being the gastrin-releasing peptide (GRP). GRP antagonists have been used to inhibit the proliferation of cancer cells. Here, I demonstrate that GRP silencing induced apoptosis in neuroblastoma cells and, in combination, allowed the usage of sublethal doses of chemotherapeutic drugs to elicit responses similar to lethal doses of the same drugs when used alone. GRP silencing also decreased tumorigenesis in vitro and suppressed liver metastasis in vivo. Moreover, GRP silencing increased PTEN levels with a simultaneous inhibition of AKT/mTOR/FAK activation in neuroblastoma cells. Interestingly, PTEN overexpression inhibited GRP-mediated neuroblastoma progression in vitro. This placed PTEN as a critical negative regulator of the oncogenic effects of GRP in neuroblastoma progression. This study provides a rationale for the use of GRP antagonists in patients with aggressive, refractory neuroblastomas.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08202013-144426 |
| Date | 04 September 2013 |
| Creators | Paul, Pritha |
| Contributors | Ambra Pozzi, Ph.D., Chin Chiang, Ph.D., Michael Freeman, Ph.D., Dai H. Chung, M.D. |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-08202013-144426/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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