Date of Award

1-1-2016

Embargo Period

1-1-2019

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology

College

College of Graduate Studies

First Advisor

Jennifer S. Isaacs

Second Advisor

Phil Howe

Third Advisor

Steve Ethier

Fourth Advisor

Joe Blumer

Fifth Advisor

Rick Drake

Abstract

While the majority of prostate cancer remains localized with a relatively high survival rate, one of the over-arching clinical challenges of prostate cancer is identifying the men who are most likely to progress from localized, indolent disease to metastatic, aggressive disease. Given that the majority of prostate cancer-related deaths are due to metastatic progression to the bone, understanding the initiating factors of cancer progression and the mechanisms involved are critical to the development of novel prognostic tools as well as potential therapies. Our studies have implicated extracellular heat shock protein 90 (eHsp90) as a novel signaling factor that can potentiate prostate cancer progression. We developed and utilized a lentiviral-based approach to enforce eHsp90 secretion in a model of localized PCa. We assessed known metrics for cancer invasion such motility, anoikis resistance, and modulation of key proteins as well as utilizing a pseudo-orthotopic model to confirm our results in vivo. We further assessed the development of stem-like cells, which have been shown to be involved in cancer progression via flow cytometry and spheroid formation. We herein demonstrate that eHsp90 activates the MAPK/ERK signaling pathway in order to promote upregulation and activation of EZH2 to drive events in prostate cancer progression. We further define a critical role for EZH2 in eHsp90-driven invasion in vivo. Moreover, we find that eHsp90-supported increases in stem-like behavior relies on a complex signaling pathway, which may provide evidence for the existence of multiple sub-populations of stem-like cells within our models. Overall, our data presented demonstrate that eHsp90 is a driver of prostate cancer progression through the activation of MAPK/ERK signaling and EZH2 activity.

Rights

All rights reserved. Copyright is held by the author.

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