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Access Type

WSU Access

Date of Award

1-1-2010

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmacology

First Advisor

Raymond R. Mattingly

Abstract

Prenylation pathways have been targeted via several different compounds that inhibit farnesyl transferase (FTase) and/or geranylgeranyl transferase (GGTase) enzymes in many cellular and animal models of cancer. Some of these have also been evaluated in clinical trials with limited success. Multiple mechanisms of action have been elucidated for such compounds, including cell cycle arrest, proteasome inhibition, apoptosis and most recently, autophagy. However, there is still an urgent need of effective agents of this class of anti-tumor therapeutics. In this dissertation, I sought to delve into this issue by characterizing our novel prenylation inhibitors and their potential as anti-tumor agents. Novel compounds, GGTI-2Z and FTI-1, were used in combination with lovastatin in STS-26T malignant peripheral nerve sheath tumor (MPNST) cells. We found that GGTI-2Z/lovastatin inhibit proliferation, cause cell cycle arrest in the G1 phase and induce autophagy in STS-26T MPNST cells. FTI-1/lovastatin not only inhibit proliferation and cause cell cycle arrest, but also induce an aborted autophagic program followed by non-apoptotic cell death in STS-26T cells. This distinct phenotype observed with FTI-1/lovastatin is the consequence of their action on the lysosomal trafficking of proteins. The compounds impaired procathepsin trafficking via the endocytic pathway along with degradation of the lysosomal protein, LAMP-2, which is required for autophagosome-lysosome fusion. These effects consequently lead to altered protein turnover and hence non-apoptotic cell death. Our observations identify a novel mechanism of action of GGTIs. We also show that autophagic cell death can be a consequence of an aborted autophagic program versus excessive autophagy. This mechanism also suggests that prenylated proteins may play an important role in a complete autophagic response and blocking their prenylation may interfere with this function of these proteins. Finally, the strategy of combination therapy with low doses of a statin and an FTI or a GGTI compound may serve as a useful tool to develop better therapeutic regimen for many cancers and other Rab-associated trafficking disorders.