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 prostate cancer. To test this hypothesis, we leveraged syngeneic mouse models to demonstrate that CAMKK2 intact tumors grow slower in Camkk2-/- host mice compared to Camkk2+/+ controls and again were characterized by smaller cancer cells (as well as increased cell death) and decreased mTOR signaling. This experiment confirmed novel nonautonomous roles of CAMKK2 and further supports the rational to target CAMKK2 in prostate cancer. Moreover, it suggests that systemic targeting of CAMKK2 may have additional benefits for patients by reversing symptoms of metabolic syndrome, a common comorbidity for men treated with standard of care ADT.
To identify AMPK targets that could be promoting prostate cancer progression in patients in an unbiased manner, we applied an improved AMPK substrate motif to clinical phosphoproteomic data to find potential AMPK substrates enriched in advanced prostate cancers. The protein adipose triglyceride lipase (ATGL), the rate-limiting step in the breakdown of triglycerides, was revealed as the top phosphorylated AMPK substrate in metastatic, castration-resistant prostate cancer compared to benign prostate or primary, hormone-naïve prostate cancer patient samples. Here, we confirmed that CAMKK2-AMPK signaling phosphorylates and increases the activity of ATGL. Importantly, using a combination of molecular, pharmacological, and genetic approaches, we also demonstrated that ATGL increased prostate cancer migration, proliferation and invasion in vitro and in vivo in diverse AR+ and AR- prostate cancer models. We further identified a metabolic shift that occurred following ATGL inhibition that could be exploited therapeutically.
Collectively, this work has identified novel autonomous and non-cancer cell-autonomous roles for CAMKK2 signaling in prostate cancer, underscoring its potential as a new therapeutic target. While more work is needed to further characterize ATGL’s regulation and roles in prostate cancer, my data indicates that targeting upstream kinases such as CAMKK2 could not only have anti-cancer activity, but also counteract some of the common comorbidities for prostate cancer patients.
","abstract_html":"<p>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 <em>CAMKK2</em>, a gene coding for the serine/threonine kinase Ca<sup>2+/</sup>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.</p> <p>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?</p> <p>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 <em>Camkk2</em> 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 <em>Camkk2-/- </em>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 <em>Camkk2</em> also led to decreased circulating insulin levels, suggested a potential cancer cell extrinsic role for CAMKK2 in prostate cancer. To test this hypothesis, we leveraged syngeneic mouse models to demonstrate that CAMKK2 intact tumors grow slower in <em>Camkk2</em>-/- host mice compared to <em>Camkk2</em>+/+ controls and again were characterized by smaller cancer cells (as well as increased cell death) and decreased mTOR signaling. This experiment confirmed novel nonautonomous roles of CAMKK2 and further supports the rational to target CAMKK2 in prostate cancer. Moreover, it suggests that systemic targeting of CAMKK2 may have additional benefits for patients by reversing symptoms of metabolic syndrome, a common comorbidity for men treated with standard of care ADT.</p> <p>To identify AMPK targets that could be promoting prostate cancer progression in patients in an unbiased manner, we applied an improved AMPK substrate motif to clinical phosphoproteomic data to find potential AMPK substrates enriched in advanced prostate cancers. The protein adipose triglyceride lipase (ATGL), the rate-limiting step in the breakdown of triglycerides, was revealed as the top phosphorylated AMPK substrate in metastatic, castration-resistant prostate cancer compared to benign prostate or primary, hormone-naïve prostate cancer patient samples. Here, we confirmed that CAMKK2-AMPK signaling phosphorylates and increases the activity of ATGL. Importantly, using a combination of molecular, pharmacological, and genetic approaches, we also demonstrated that ATGL increased prostate cancer migration, proliferation and invasion <em>in vitro</em> and <em>in vivo</em> in diverse AR+ and AR- prostate cancer models. We further identified a metabolic shift that occurred following ATGL inhibition that could be exploited therapeutically.</p> <p>Collectively, this work has identified novel autonomous and non-cancer cell-autonomous roles for CAMKK2 signaling in prostate cancer, underscoring its potential as a new therapeutic target. While more work is needed to further characterize ATGL’s regulation and roles in prostate cancer, my data indicates that targeting upstream kinases such as CAMKK2 could not only have anti-cancer activity, but also counteract some of the common comorbidities for prostate cancer patients.</p>","abstract_has_math":false,"creators":["Awad, Dominik","0000-0002-7386-2061
"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Daniel E. Frigo, Ph.D.","Sue-Hwa Lin, Ph.D.","Mary C. Farach-Carson, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-08-01T07:00:00Z","date_published":"2022-08-01T07:00:00Z","updated_at":"2026-07-24T05:49:16Z","subjects":["AR","CAMKK2","AMPK","ATGL","PNPLA2","METABOLISM","PROSTATE CANCER","Biochemistry","Cancer Biology","Cell Biology","Molecular Biology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1194","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Daniel E. Frigo, Ph.D.","Sue-Hwa Lin, Ph.D.","Mary C. Farach-Carson, Ph.D."]},{"key":"dc:creator","label":"Author","values":["Awad, Dominik","0000-0002-7386-2061
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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 prostate cancer. To test this hypothesis, we leveraged syngeneic mouse models to demonstrate that CAMKK2 intact tumors grow slower in Camkk2-/- host mice compared to Camkk2+/+ controls and again were characterized by smaller cancer cells (as well as increased cell death) and decreased mTOR signaling. This experiment confirmed novel nonautonomous roles of CAMKK2 and further supports the rational to target CAMKK2 in prostate cancer. Moreover, it suggests that systemic targeting of CAMKK2 may have additional benefits for patients by reversing symptoms of metabolic syndrome, a common comorbidity for men treated with standard of care ADT.
To identify AMPK targets that could be promoting prostate cancer progression in patients in an unbiased manner, we applied an improved AMPK substrate motif to clinical phosphoproteomic data to find potential AMPK substrates enriched in advanced prostate cancers. The protein adipose triglyceride lipase (ATGL), the rate-limiting step in the breakdown of triglycerides, was revealed as the top phosphorylated AMPK substrate in metastatic, castration-resistant prostate cancer compared to benign prostate or primary, hormone-naïve prostate cancer patient samples. Here, we confirmed that CAMKK2-AMPK signaling phosphorylates and increases the activity of ATGL. Importantly, using a combination of molecular, pharmacological, and genetic approaches, we also demonstrated that ATGL increased prostate cancer migration, proliferation and invasion in vitro and in vivo in diverse AR+ and AR- prostate cancer models. We further identified a metabolic shift that occurred following ATGL inhibition that could be exploited therapeutically.
Collectively, this work has identified novel autonomous and non-cancer cell-autonomous roles for CAMKK2 signaling in prostate cancer, underscoring its potential as a new therapeutic target. While more work is needed to further characterize ATGL’s regulation and roles in prostate cancer, my data indicates that targeting upstream kinases such as CAMKK2 could not only have anti-cancer activity, but also counteract some of the common comorbidities for prostate cancer patients.
"]},{"key":"dc:title","label":"Title","values":["Regulation of Systemic and Cellular Metabolism In Prostate Cancer By Camkk2 and Elucidation of Atgl’S Role In Disease Progression"]}]}],"canonical_facts":{"dc:contributor":["Daniel E. Frigo, Ph.D.","Sue-Hwa Lin, Ph.D.","Mary C. Farach-Carson, Ph.D."],"dc:creator":["Awad, Dominik","0000-0002-7386-2061
"],"dc:date.available":["2025-06-02T07:00:00Z"],"dc:description.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 prostate cancer. To test this hypothesis, we leveraged syngeneic mouse models to demonstrate that CAMKK2 intact tumors grow slower in Camkk2-/- host mice compared to Camkk2+/+ controls and again were characterized by smaller cancer cells (as well as increased cell death) and decreased mTOR signaling. This experiment confirmed novel nonautonomous roles of CAMKK2 and further supports the rational to target CAMKK2 in prostate cancer. Moreover, it suggests that systemic targeting of CAMKK2 may have additional benefits for patients by reversing symptoms of metabolic syndrome, a common comorbidity for men treated with standard of care ADT.
To identify AMPK targets that could be promoting prostate cancer progression in patients in an unbiased manner, we applied an improved AMPK substrate motif to clinical phosphoproteomic data to find potential AMPK substrates enriched in advanced prostate cancers. The protein adipose triglyceride lipase (ATGL), the rate-limiting step in the breakdown of triglycerides, was revealed as the top phosphorylated AMPK substrate in metastatic, castration-resistant prostate cancer compared to benign prostate or primary, hormone-naïve prostate cancer patient samples. Here, we confirmed that CAMKK2-AMPK signaling phosphorylates and increases the activity of ATGL. Importantly, using a combination of molecular, pharmacological, and genetic approaches, we also demonstrated that ATGL increased prostate cancer migration, proliferation and invasion in vitro and in vivo in diverse AR+ and AR- prostate cancer models. We further identified a metabolic shift that occurred following ATGL inhibition that could be exploited therapeutically.
Collectively, this work has identified novel autonomous and non-cancer cell-autonomous roles for CAMKK2 signaling in prostate cancer, underscoring its potential as a new therapeutic target. While more work is needed to further characterize ATGL’s regulation and roles in prostate cancer, my data indicates that targeting upstream kinases such as CAMKK2 could not only have anti-cancer activity, but also counteract some of the common comorbidities for prostate cancer patients.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1194"],"dc:subject":["AR","CAMKK2","AMPK","ATGL","PNPLA2","METABOLISM","PROSTATE CANCER","Biochemistry","Cancer Biology","Cell Biology","Molecular Biology"],"dc:title":["Regulation of Systemic and Cellular Metabolism In Prostate Cancer By Camkk2 and Elucidation of Atgl’S Role In Disease Progression"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:49:16Z"}