Regulation of Systemic and Cellular Metabolism In Prostate Cancer By Camkk2 and Elucidation of Atgl’S Role In Disease Progression
type: CreativeWork
description: The androgen receptor (AR) is the major driver of prostate cancer; hence, men with progressing disease are treated with androgen deprivation therapy (ADT). However, the majority of patients will relapse within 2-3 years due to multiple AR reactivation mechanisms. Thus, AR and the processes downstream of the receptor remain central drivers of prostate cancer. A direct target of AR is CAMKK2, a gene coding for the serine/threonine kinase Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2), a protein upregulated in advanced prostate cancer. CAMKK2 modulates many of its pathological effects through the phosphorylation and activation of the 5' AMP-activated protein kinase (AMPK), a master regulator of metabolism that was first described in cancer as a tumor suppressor, but was later shown to possess context-dependent, oncogenic roles. Therefore, it is important to distinguish the oncogenic pathways modulated by AMPK to determine how best to target this signaling network. The work in this dissertation aims to answer two questions: 1) Can we systemically target CAMKK2 to treat prostate cancer? 2) What are the downstream targets of CAMKK2-AMPK signaling in prostate cancer that are oncogenic drivers and can they be targeted therapeutically? To answer if CAMKK2 can be targeted systemically, we utilized the TRansgenic Adenocarcinoma Mouse Prostate (TRAMP) genetic mouse model and found that germline deletion of Camkk2 indeed slows, but does not stop, primary prostate tumorigenesis. Interestingly, high-fat diet-fed TRAMP mice, a model of obesity-driven prostate cancer progression, exhibited CAMKK2-dependent metastatic colonization of neuroendocrine prostate cancer in the lungs. Tumors in Camkk2-/- mice surprisingly demonstrated a decrease in cell size that is likely due to decreased mTOR signaling. These data, combined with the observation that loss of Camkk2 also led to decreased circulating insulin levels, suggested a potential cancer cell extrinsic role for CAMKK2 in p…
abstract: The androgen receptor (AR) is the major driver of prostate cancer; hence, men with progressing disease are treated with androgen deprivation therapy (ADT). However, the majority of patients will relapse within 2-3 years due to multiple AR reactivation mechanisms. Thus, AR and the processes downstream of the receptor remain central drivers of prostate cancer. A direct target of AR is CAMKK2, a gene coding for the serine/threonine kinase Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2), a protein upregulated in advanced prostate cancer. CAMKK2 modulates many of its pathological effects through the phosphorylation and activation of the 5' AMP-activated protein kinase (AMPK), a master regulator of metabolism that was first described in cancer as a tumor suppressor, but was later shown to possess context-dependent, oncogenic roles. Therefore, it is important to distinguish the oncogenic pathways modulated by AMPK to determine how best to target this signaling network. The work in this dissertation aims to answer two questions: 1) Can we systemically target CAMKK2 to treat prostate cancer? 2) What are the downstream targets of CAMKK2-AMPK signaling in prostate cancer that are oncogenic drivers and can they be targeted therapeutically? To answer if CAMKK2 can be targeted systemically, we utilized the TRansgenic Adenocarcinoma Mouse Prostate (TRAMP) genetic mouse model and found that germline deletion of Camkk2 indeed slows, but does not stop, primary prostate tumorigenesis. Interestingly, high-fat diet-fed TRAMP mice, a model of obesity-driven prostate cancer progression, exhibited CAMKK2-dependent metastatic colonization of neuroendocrine prostate cancer in the lungs. Tumors in Camkk2-/- mice surprisingly demonstrated a decrease in cell size that is likely due to decreased mTOR signaling. These data, combined with the observation that loss of Camkk2 also led to decreased circulating insulin levels, suggested a potential cancer cell extrinsic role for CAMKK2 in p…
author: Awad, Dominik
author: 0000-0002-7386-2061
keywords: AR, CAMKK2, AMPK, ATGL, PNPLA2, METABOLISM, PROSTATE CANCER, Biochemistry, Cancer Biology, Cell Biology, Molecular Biology
date published: 2022-08-01T07:00:00Z
date modified: 2026-07-24T05:49:16Z
provider: University of Texas Health Science Center at Houston
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Texas Health Science Center at Houston