Files and links (1)
PDFOpen Access (License Unspecified), Open Access
Dissertation
Serotonin is a survival factor for human multiple myeloma cells
Doctor of Philosophy (Ph.D.), Drexel University
Sep 2004
DOI:
https://doi.org/10.17918/00000646
Abstract
Multiple myeloma (MM) is currently an incurable hematologic malignancy. Development of novel biologically based therapies is crucial to the treatment of multiple myeloma and the avoidance of chemoresistance. This thesis provides evidence for a novel signaling system that is important for MM cell survival. Using RT-PCR, we show that the transcript encoding the rate-limiting enzyme (tryptophan hydroxylase [TPH1]) is present in the MM cells. Furthermore an enzymatic activity assay for the TPH1 was used to show that tryptophan is actively converted to serotonin in MM cells. Immunofluorescence staining studies also show that MM cells store serotonin in, what appear to be, alpha-granules. In addition, HPLC studies demonstrate depletion of 5-HT from the tissue culture media induces the MM cells to synthesize and secrete serotonin. Finally, data indicate serotonin-responsive receptors are present on the MM cells and the 5-HT1B receptor provides a survival signal for the MM cells. Inhibition of signaling at the 5-HT1B receptor results in a loss of activated Akt and the subsequent induction of programmed cell death. Taken together, these data demonstrate that serotonin is an autocrine survival factor for human multiple myeloma cells. We also show that MM cells cannot be rescued from 5-HT1B antagonist induced apoptosis by the protective cytokine, IL-6. And, 5-HT1B antagonists are additive with the conventional chemotherapeutic agent dexamethasone. Our data not only support the existence of an autocrine role for serotonin but suggest that the serotonergic system may provide a new clinical target for treating MM patients.
Metrics
41 File views/ downloads
45 Record Views
Details
- Title
- Serotonin is a survival factor for human multiple myeloma cells
- Creators
- Harold Carter Davidson
- Contributors
- Bradford Aldrich Jameson (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xi, 175 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014970313504721