Date of Award

2008

Degree Type

Dissertation

Department

Chemistry

First Advisor

DiDonato, Joseph

Subject Headings

Cancer, Apoptosis, NF-kappa B (DNA-binding protein), NF-kappaB, IHPK2, Toll-like Receptor 5, TLR5, Nitrosylcobalamine, Nitric Oxide, TRAIL/Apo2L, Flagellin, Doxorubicin, Etoposide, VP-16, IKK, fliC, Electronic books. local

Abstract

The Rel/NF-kB family of inducible transcription factors are evolutionarily conserved structurally and functionally, from insects to humans. They are ubiquitously expressed in a number of mature cell types, playing a pivotal role regulating cell growth, differentiation and apoptosis. Under normal circumstances, the proliferation of new cells is tightly regulated, as is the programmed lifespan of most cells, occasionally however cells loose their responsiveness to growth control mechanisms, resulting in a tumor or neoplasm. Sustained or chronic inflammation has been linked to a number of pathological conditions that destroy tissue and facilitate neoplastic growth. NF-kB in part mediates the opposing signals of cell survival and cell death, associated with this response. We hypothesized that inhibition of NF-kB would inhibit tumor cell growth. A number of anti-neoplastic drugs like some pro-inflammatory cytokines can activate both the cellular apoptotic and pro-survival (via NF-kB) pathways. We demonstrate, in vitro, that the use of Nitric Oxide mitigates NF-kB activation and induces program cell death, when administered as an adjuvant with this subset of pro-inflammatory cytokines. Secondly, several front-line anti-cancer drugs activate NF-kB as a result of their mode of action, resulting in the survival of a resistant population of tumor cells. In order to abrogate this beneficial activity for the tumor cell we explore, both in vitro and in vivo, the use of Nitric Oxide to inhibit NF-kB, augmenting the efficacy of the anti-neoplastic drugs. Thirdly, we identify that the intracellular signaling kinase, Inositol Hexkisphosphate Kinase2 (IHPK2) , binds to a key component in the NF-kB signaling pathway, inhibiting NF-kB activity promoting apoptosis in tumor cells. Lastly, an in depth study investigating the major initiator of pro-inflammatory signaling during bacterial infection of cells by Salmonela sp. was in fact due to recognition of the bacterial protein flagellin by the cell surface receptor Toll-like receptor

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