Defense Date

2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

David A. Gewirtz

Abstract

In MCF-7 breast tumor cells, ionizing radiation promoted autophagy that was cytoprotective; pharmacological or genetic interference with autophagy induced by radiation resulted in growth suppression and/or cell killing (primarily by apoptosis). The hormonally active form of vitamin D, 1,25D3, also promoted autophagy in irradiated MCF-7 cells, sensitized the cells to radiation and suppressed the proliferative recovery that occurs after radiation alone. 1,25D3 also enhanced radiosensitivity and promoted autophagy in MCF7 cells that overexpress Her-2/neu as well as in p53 mutant Hs578t breast tumor cells. In contrast, 1,25D3 failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell line with low-level expression of the vitamin D receptor. Enhancement of MCF-7 cell sensitivity to radiation by 1,25D3 was not attenuated by either a pharmacological or genetic block to autophagy; this was due largely to the promotion of apoptosis via the suppression of protective autophagy that occurs in response to radiation alone. Moreover, pharmacological blockade of autophagy did not sensitize noncancerous MCF10a cells to radiation; conversely, 4T1 mouse mammary tumors were highly sensitive to pharmacological inhibition of autophagy, suggesting selective radiosensitization against cancer cell lines. The current studies are consistent with the premise that while autophagy mediates a cytoprotective function in irradiated breast tumor cells, promotion of autophagy can also confer radiosensitivity by vitamin D (1,25D3). In addition, this work highlights the technical challenge of establishing the potential cytotoxic function of autophagy in an experimental system where the cytoprotective function may be concurrently expressed.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

August 2011

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