All ETDs from UAB

Advisory Committee Chair

Champion Deivanayagam

Advisory Committee Members

Edwin Blalock

Lawrence Delucas

Peter Smith

Susan Bellis

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Aberrant hyaluronan production is frequently associated with tumors where the elevated levels of tumoral hyaluronan are often associated with higher expression levels of cellular hyaluronidases that produce saturated hyaluronan fragments with divergent pro-tumoral activities. In this thesis, we provide evidence that different hyaluronan metabolism of bacteriophage hyaluronidase (HylP) elicits distinct alteration in breast cancer cell behavior. We demonstrate through comparative analysis with bovine testicular hyaluronidase (BTH) that higher enzyme activity, specificity for hyaluronan and production of unsaturated oligosaccharides render HylP to have profound effects on growth, migration and invasion activities of breast carcinoma cells, whereas BTH and its saturated metabolites aggravate cancer cell proliferation. Our experimental data also indicate that HylP reverses hyaluronan-mediated Doxorubicin resistance, which further suggests its therapeutic potential in suppressing hyaluronan-mediated cancer progression. Functional characterization with a truncated form of HylP hyaluronidase suggests that collagen-like region in HylP may have an important role in exerting anti-cancer effects. Hence, the crystal structure of truncated phage enzyme determined as a part of this thesis work will be in use in future investigations to determine the collagenous structure in the native HylP enzyme as well as to identify the active sites of HylP, which would provide better understanding of the distinct catalytic mechanism in metabolizing hyaluronan.

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