Biomedical Sciences ETDs

Ramesh Kaini

Publication Date

5-1-2012

Abstract

Androgen deprivation therapy, one of the standard treatments for prostate cancer, induces apoptosis as well as autophagy in androgen-responsive PCa cells. As modulation of autophagy is a new paradigm for enhancing the therapeutic efficacy of various cancer therapies, we sought to determine the functions of autophagy during androgen deprivation. In this study, we confirmed that androgen removal or inhibition induces autophagy in two different hormone sensitive prostate cancer cells. Androgen deprivation also caused depletion of lipid droplets which was abrogated on inhibition of autophagy by pharmacological means (3-methyladenine, bafilomycin A1) or using a genetic approach (Atg5 siRNA). In addition, colocalization of lipid droplets and autophagic vesicles was observed in LNCaP cells, which was further enhanced by blocking the autophagic flux. These findings suggest that autophagy mediates lipid droplet degradation and lipolysis in androgen sensitive prostate cancer cells. Furthermore, inhibition of autophagy by chloroquine during androgen deprivation synergistically killed LNCaP cells in a dose and time dependent manner. We further confirmed that chloroquine caused accumulation of autophagosomes and decreased cytosolic ATP levels. Moreover, chloroquine induced apoptosis in androgen deprived LNCaP cells. These findings suggest that chloroquine may be used as an adjuvant in hormone therapy to improve therapeutic efficacy.

Keywords

"Autophagy, Prostate cancer, Lipid droplets, Androgen deprivation, Chloroquine"

Sponsors

Department of defense Prostate cancer research program

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Bisoffi, Marco

Second Committee Member

Deretic, Vojo

Third Committee Member

Sillerud, Laurel

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