Systemic ablation of Camkk2 impairs metastatic colonization and improves insulin sensitivity in TRAMP mice : Evidence for cancer cell-extrinsic CAMKK2 functions in prostate cancer
Journal article
Pulliam, Thomas L., Awad, Dominik, Han, Jenny J., Murray, Mollianne M., Ackroyd, Jeffrey J., Goli, Pavithr, Oakhill, Jonathan S., Scott, John W., Ittmann, Michael M. and Frigo, Daniel E.. (2022). Systemic ablation of Camkk2 impairs metastatic colonization and improves insulin sensitivity in TRAMP mice : Evidence for cancer cell-extrinsic CAMKK2 functions in prostate cancer. Cells. 11(12), p. Article 1890. https://doi.org/10.3390/cells11121890
Authors | Pulliam, Thomas L., Awad, Dominik, Han, Jenny J., Murray, Mollianne M., Ackroyd, Jeffrey J., Goli, Pavithr, Oakhill, Jonathan S., Scott, John W., Ittmann, Michael M. and Frigo, Daniel E. |
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Abstract | 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. |
Keywords | prostate cancer; CAMKK2; obesity; metastasis; TRAMP; high-fat diet; insulin; mTOR; neuroendocrine prostate cancer (NEPC) |
Year | 2022 |
Journal | Cells |
Journal citation | 11 (12), p. Article 1890 |
Publisher | MDPI AG |
Multidisciplinary Digital Publishing Institute (MDPI AG) | |
ISSN | 2073-4409 |
Digital Object Identifier (DOI) | https://doi.org/10.3390/cells11121890 |
PubMed ID | 35741020 |
Scopus EID | 2-s2.0-85132686318 |
PubMed Central ID | PMC9221545 |
Open access | Published as ‘gold’ (paid) open access |
Page range | 1-19 |
Funder | National Institutes of Health (NIH), United States of America |
American Cancer Society | |
Mike Slive Foundation for Prostate Cancer Research | |
National Health and Medical Research Council (NHMRC) | |
American Legion Auxiliary | |
MD Anderson Cancer Center (MDACC) | |
Baylor College of Medicine | |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 10 Jun 2022 |
Publication process dates | |
Accepted | 07 Jun 2022 |
Deposited | 01 Mar 2023 |
Grant ID | NIHR01CA184208 |
P50CA140388 | |
RSG-16-084-01-TBE | |
GNT1138102 | |
GNT1145265 | |
P30CA016672 | |
UM1HG006348 | |
R01DK114356 | |
R01HL130249 |
https://acuresearchbank.acu.edu.au/item/8yw33/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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Publisher's version
OA_Pulliam_2022_Systemic_ablation_of_Camkk2_impairs_metastatic.pdf | |
License: CC BY 4.0 | |
File access level: Open |
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