Indiana University-Purdue University Indianapolis (IUPUI) / The overexpression of the multi-domain enzyme fatty acid synthase
(FASN) has long been associated with poor clinical prognosis and treatment
outcome in various cancers. Previous research in the Zhang lab has determined
a role for FASN in mediating increases in non-homologous end-joining (NHEJ)
DNA double-strand break repair activity allowing for increased cancer cell
survival, and this mechanism was found to involve inhibition of NF-kB/p65. The
mechanism responsible for the regulation of NF-kB/p65 by FASN in cancer cells,
however, remains unknown. To this end, I was able to determine that FASN
negatively regulates both the expression and activity of NF-kB/p65 in breast
cancer cells, and that this effect was likely mediated by the 16-carbon saturated
fatty acid palmitate, the end product of FASN catalytic activity. Specifically, FASN
was found to negatively regulate p65 expression by disrupting its protein stability
as a result of an increase in poly-ubiquitination of p65 protein and subsequent
proteasomal degradation. Further, I found that the phosphorylation site Thr254 of
p65 is involved in the regulation of p65 protein stability by FASN, in that mutation
of this residue resulted in a disruption in p65 stability. Finally, I was able to
determine that FASN likely inhibits the ability of the peptidyl-prolyl cis/trans
isomerase Pin1 to assist in maintaining p65 stability, in that both siRNA knockdown and pharmacological inhibition of Pin1 resulted in a reduction of p65
expression in FASN shRNA knockdown cells. The determination of this signaling
mechanism serves to expand our understanding of the role of FASN in breast
cancer cells and has the potential to assist in uncovering more effective ways to
target the oncogenic FASN pathway to kill breast tumor cells and to overcome
resistance to drug treatment.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/22284 |
| Date | 02 1900 |
| Creators | Barlow, Lincoln James |
| Contributors | Lu, Tao, Zhang, Jian-Ting, Fehrenbacher, Jill, Herbert, Brittney-Shea, Safa, Ahmad |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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