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Functions of autophagy in lipid homeostasis and survival in androgen-dependent prostate cancer cells

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Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/20833

Functions of autophagy in lipid homeostasis and survival in androgen-dependent prostate cancer cells

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Title: Functions of autophagy in lipid homeostasis and survival in androgen-dependent prostate cancer cells
Author: Kaini, Ramesh
Advisor(s): Hu, Chien-An
Committee Member(s): Bisoffi, Marco
Deretic, Vojo
Sillerud, Laurel
Department: University of New Mexico. Biomedical Sciences Graduate Program
Subject: Autophagy, Prostate cancer, Lipid droplets, Androgen deprivation, Chloroquine
LC Subject(s): Antiandrogens--Therapeutic use.
Prostate--Cancer--Hormone therapy. .
Autophagic vacuoles.
Chloroquine--Therapeutic use.
Degree Level: Doctoral
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.
Graduation Date: May 2012
URI: http://hdl.handle.net/1928/20833


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