Author ORCID Identifier

Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation

Experimental Therapeutics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Daniel E. Frigo

Committee Member

Nancy L. Weigel

Committee Member

William Plunkett

Committee Member

Jefferey A. Frost

Committee Member

Shuxing Zhang


The androgen receptor (AR) is the primary driver of prostate cancer and, therefore, AR-regulated signaling events are essential for the development and progression of the disease. Despite their initial effectiveness, drugs targeting AR eventually fail as sustained inhibition of receptor activity remains a challenge. Previously, Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was identified as an essential downstream component of AR signaling in prostate cancer that correspondingly tracked with disease progression. While the importance of CAMKK2 in AR-mediated prostate cancer progression has been established, our understanding of the events downstream that promote the disease remains incomplete. Here, I elucidated two AR-CAMKK2-regulated kinase signaling cascades which are hypothesized to promote disease progression and therefore represent alternative therapeutic targets in castration-resistant prostate cancer (CRPC).

First, I identified Unc-51 like autophagy activating kinase 1 (ULK1), an important autophagic initiator, as one of downstream effectors regulated by AR-CAMKK2-5’-AMP-activated protein kinase (AMPK) signaling. CAMKK2-induced protective autophagy is partially dependent on the phosphorylation of ULK1 at serine 555, which is required for prostate cancer cell growth. Accordingly, inhibition of CAMKK2-AMPK-ULK1 signaling by molecular, genetic and/or pharmacological inhibitors decreased autophagy and cell growth in CRPC tumor growth.

Second, I investigated the role of AR-CAMKK2 on the activation of the transcription factor cyclic-AMP response element-binding protein (CREB). Cancer cell-intrinsic CAMKK2 signaling promoted CRPC in part through increasing the activity of CREB. Molecularly, this was shown to occur through the calcium/calmodulin-dependent protein kinase I-mediated phosphorylation of CREB on its serine 133 activation site. I also determined a functional redundancy between two CREB family members, CREB1 and Activating Transcription Factor 1. Deletion of both genes impaired transcriptional activity and maximal prostate cancer cell proliferation in tissue culture and tumor initiation as well as growth in CRPC. Therapeutically, pharmacological targeting of CREB by 666-15 effectively blocked cell cycle and inhibited cell/tumor growth without significant toxicity and was able to decrease the growth of CRPC tumors resistant to second-generation antiandrogens.

Collectively, I have leveraged orthogonal molecular, genetic and pharmacological approaches to delineate how AR-CAMKK2 signaling drives prostate cancer progression and define potential new therapeutic strategies for targeting this oncogenic cascade in CRPC.


Prostate cancer, AR-CAMKK2 pathway, ULK1, CREB



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