Regulation and role of CAMKK2 in prostate cancer

Pulliam, Thomas L.; Goli, Pavithr; Awad, Dominik; Lin, Chenchu; Wilkenfeld, Sandi R.; Frigo, Daniel E.

doi:10.1038/s41585-022-00588-z

Cited by 26 publications

(19 citation statements)

References 174 publications

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“…Triptolide-CAMKK2-AMPK 3. AR-CAMKK2-Lipogenesis [16][17][18][19][20] Pancreatic cancer CaMKK2/ARHGEF2 [21] Infectious Disease…”

Section: Camkk2 Inhibition Accelerates Bone Healingmentioning

confidence: 99%

“…Triptolide-CAMKK2-AMPK 3. AR-CAMKK2-Lipogenesis [16][17][18][19][20] Pancreatic cancer CaMKK2/ARHGEF2 [21] Infectious The compound STO-609 has demonstrated CAMKK2 inhibition in both cellular and in vivo settings [7,31,44]. However, it has also been shown to inhibit additional kinases such as CK2, AMPK, MNK1, PIM2, PIM3, DYRK2, DYRK3, and ERK8, which at high treatment concentrations could lead to confounding results.…”

Section: Camkk2 Inhibition Accelerates Bone Healingmentioning

confidence: 99%

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SGC-CAMKK2-1: A chemical probe for CAMKK2

Wells

Liang

Pulliam

et al. 2022

Preprint

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The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2.

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“…Triptolide-CAMKK2-AMPK 3. AR-CAMKK2-Lipogenesis [16][17][18][19][20] Pancreatic cancer CaMKK2/ARHGEF2 [21] Infectious Disease…”

Section: Camkk2 Inhibition Accelerates Bone Healingmentioning

confidence: 99%

Section: Camkk2 Inhibition Accelerates Bone Healingmentioning

confidence: 99%

SGC-CAMKK2-1: A chemical probe for CAMKK2

Wells

Liang

Pulliam

et al. 2022

Preprint

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“…The AR is certainly the most exploited molecular target for the treatment of prostate cancer also for PROTACs [ 24 , 25 ]. Importantly, the structure is available for two of the three PROTAC molecules included in clinical trials aimed at the treatment of prostate cancer, specifically ARV-110 and ARV-766 (both from Arvinas, Figure 2 [ 4 ]).…”

Section: Introductionmentioning

confidence: 99%

Proteolysis Targeting Chimeric Molecules: Tuning Molecular Strategies for a Clinically Sound Listening

Pedrucci

Pappalardo

Marzaro

et al. 2022

IJMS

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From seminal evidence in the early 2000s, the opportunity to drive the specific knockdown of a protein of interest (POI) through pharmacological entities called Proteolysis Targeting Chimeric molecules, or PROTACs, has become a possible therapeutic option with the involvement of these compounds in clinical trials for cancers and autoimmune diseases. The fulcrum of PROTACs pharmacodynamics is to favor the juxtaposition between an E3 ligase activity and the POI, followed by the ubiquitination of the latter and its degradation by the proteasome system. In the face of an apparently modular design of these drugs, being constituted by an E3 ligase binding moiety and a POI-binding moiety connected by a linker, the final structure of an efficient PROTAC degradation enhancer often goes beyond the molecular descriptors known to influence the biological activity, specificity, and pharmacokinetics, requiring a rational improvement through appropriate molecular strategies. Starting from the description of the basic principles underlying the activity of the PROTACs to the evaluation of the strategies for the improvement of pharmacodynamics and pharmacokinetics and rational design, this review examines the molecular elements that have been shown to be effective in allowing the evolution of these compounds from interesting proof of concepts to potential aids of clinical interest.

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“…CAMKK2 is a serine/threonine kinase that facilitates cancer progression primarily via the phosphorylation and activation of downstream targets such as CAMKI, CAMKIV, and AMPK [ 6 , 7 , 8 ] (Reviewed in detail in [ 9 ]). To date, the majority of cancer cell-intrinsic effects of CAMKK2 in prostate cancer have been attributed to AMP-dependent protein kinase (AMPK), which can mediate prostate cancer cell proliferation, migration, and invasion (Reviewed in detail in [ 10 ]).…”

Section: Introductionmentioning

confidence: 99%

“…To date, the majority of cancer cell-intrinsic effects of CAMKK2 in prostate cancer have been attributed to AMP-dependent protein kinase (AMPK), which can mediate prostate cancer cell proliferation, migration, and invasion (Reviewed in detail in [ 10 ]). While CAMKK2 has also been described to signal through CAMKI, CAMKIV, and occasionally AKT, it is currently unknown if these alternative CAMKK2 substrates have roles in prostate cancer [ 9 ]. CAMKK2’s oncogenic roles in prostate cancer cell biology have logically led to investigations into CAMKK2’s pro-cancer roles in vivo.…”

Section: Introductionmentioning

confidence: 99%

Systemic Ablation of Camkk2 Impairs Metastatic Colonization and Improves Insulin Sensitivity in TRAMP Mice: Evidence for Cancer Cell-Extrinsic CAMKK2 Functions in Prostate Cancer

Pulliam

Awad

Han

et al. 2022

Cells

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Despite early studies linking calcium-calmodulin protein kinase kinase 2 (CAMKK2) to prostate cancer cell migration and invasion, the role of CAMKK2 in metastasis in vivo remains unclear. Moreover, while CAMKK2 is known to regulate systemic metabolism, whether CAMKK2’s effects on whole-body metabolism would impact prostate cancer progression and/or related comorbidities is not known. Here, we demonstrate that germline ablation of Camkk2 slows, but does not stop, primary prostate tumorigenesis in the TRansgenic Adenocarcinoma Mouse Prostate (TRAMP) genetic mouse model. Consistent with prior epidemiological reports supporting a link between obesity and prostate cancer aggressiveness, TRAMP mice fed a high-fat diet exhibited a pronounced increase in the colonization of lung metastases. We demonstrated that this effect on the metastatic spread was dependent on CAMKK2. Notably, diet-induced lung metastases exhibited a highly aggressive neuroendocrine phenotype. Concurrently, Camkk2 deletion improved insulin sensitivity in the same mice. Histological analyses revealed that cancer cells were smaller in the TRAMP;Camkk2−/− mice compared to TRAMP;Camkk2+/+ controls. Given the differences in circulating insulin levels, a known regulator of cell growth, we hypothesized that systemic CAMKK2 could promote prostate cancer cell growth and disease progression in part through cancer cell-extrinsic mechanisms. Accordingly, host deletion of Camkk2 impaired the growth of syngeneic murine prostate tumors in vivo, confirming nonautonomous roles for CAMKK2 in prostate cancer. Cancer cell size and mTOR signaling was diminished in tumors propagated in Camkk2-null mice. Together, these data indicate that, in addition to cancer cell-intrinsic roles, CAMKK2 mediates prostate cancer progression via tumor-extrinsic mechanisms. Further, we propose that CAMKK2 inhibition may also help combat common metabolic comorbidities in men with advanced prostate cancer.

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Regulation and role of CAMKK2 in prostate cancer

Cited by 26 publications

References 174 publications

SGC-CAMKK2-1: A chemical probe for CAMKK2

SGC-CAMKK2-1: A chemical probe for CAMKK2

Proteolysis Targeting Chimeric Molecules: Tuning Molecular Strategies for a Clinically Sound Listening

Systemic Ablation of Camkk2 Impairs Metastatic Colonization and Improves Insulin Sensitivity in TRAMP Mice: Evidence for Cancer Cell-Extrinsic CAMKK2 Functions in Prostate Cancer

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