PMID- 30242113 OWN - NLM STAT- MEDLINE DCOM- 20191007 LR - 20220720 IS - 1538-7445 (Electronic) IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 78 IP - 24 DP - 2018 Dec 15 TI - CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis. PG - 6747-6761 LID - 10.1158/0008-5472.CAN-18-0585 [doi] AB - : New targets are required for treating prostate cancer, particularly castrate-resistant disease. Previous studies reported that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) expression is increased in human prostate cancer. Here, we show that Camkk2 deletion or pharmacologic inhibition protects against prostate cancer development in a preclinical mouse model that lacks expression of prostate-specific Pten. In contrast, deletion of AMP-activated protein kinase (Ampk) beta1 resulted in earlier onset of adenocarcinoma development. These findings suggest for the first time that Camkk2 and Ampk have opposing effects in prostate cancer progression. Loss of CAMKK2 in vivo or in human prostate cancer cells reduced the expression of two key lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase. This reduction was mediated via a posttranscriptional mechanism, potentially involving a decrease in protein translation. Moreover, either deletion of CAMKK2 or activation of AMPK reduced cell growth in human prostate cancer cells by inhibiting de novo lipogenesis. Activation of AMPK in a panel of human prostate cancer cells inhibited cell proliferation, migration, and invasion as well as androgen-receptor signaling. These findings demonstrate that CAMKK2 and AMPK have opposing effects on lipogenesis, providing a potential mechanism for their contrasting effects on prostate cancer progression in vivo. They also suggest that inhibition of CAMKK2 combined with activation of AMPK would offer an efficacious therapeutic strategy in treatment of prostate cancer. SIGNIFICANCE: These findings show that CAMKK2 and its downstream target AMPK have opposing effects on prostate cancer development and raise the possibility of a new combined therapeutic approach that inhibits CAMKK2 and activates AMPK. CI - (c)2018 American Association for Cancer Research. FAU - Penfold, Lucy AU - Penfold L AD - MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom. FAU - Woods, Angela AU - Woods A AD - MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom. FAU - Muckett, Phillip AU - Muckett P AD - MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom. FAU - Nikitin, Alexander Yu AU - Nikitin AY AUID- ORCID: 0000-0002-3729-7982 AD - Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, New York. FAU - Kent, Tera R AU - Kent TR AD - Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, New York. FAU - Zhang, Shuai AU - Zhang S AD - MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom. FAU - Graham, Rebecca AU - Graham R AD - MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom. FAU - Pollard, Alice AU - Pollard A AD - MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom. FAU - Carling, David AU - Carling D AD - MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom. dcarling@imperial.ac.uk. AD - Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital, London, United Kingdom. LA - eng GR - MC_U120027537/MRC_/Medical Research Council/United Kingdom GR - MRF_MRF-023-0001-S-PENFO/MRF/MRF/United Kingdom GR - MRF_MRF-023-0003-RG-PENFO/MRF/MRF/United Kingdom GR - R01 CA197160/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180921 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (AR protein, human) RN - 0 (Benzimidazoles) RN - 0 (Naphthalimides) RN - 0 (Receptors, Androgen) RN - 0 (STO 609) RN - EC 2.7.11.1 (PRKAB1 protein, human) RN - EC 2.7.11.1 (Prkab1 protein, mouse) RN - EC 2.7.11.17 (CAMKK2 protein, human) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase) RN - EC 2.7.11.17 (Camkk2 protein, mouse) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/*genetics MH - Adenocarcinoma/genetics MH - Animals MH - Benzimidazoles/chemistry MH - CRISPR-Cas Systems MH - Calcium-Calmodulin-Dependent Protein Kinase Kinase/*genetics MH - Cell Cycle MH - Cell Line, Tumor MH - Cell Movement MH - Cell Proliferation MH - Cell Survival MH - Female MH - Gene Deletion MH - Humans MH - *Lipogenesis MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Naphthalimides/chemistry MH - Neoplasm Invasiveness MH - Phosphorylation MH - Prostatic Neoplasms/genetics/*pathology MH - Receptors, Androgen/genetics MH - Signal Transduction PMC - PMC6295249 MID - NIHMS1508049 COIS- Disclosure of Potential Conflicts of Interest The authors declare that there are no potential conflicts of interest. EDAT- 2018/09/23 06:00 MHDA- 2019/10/08 06:00 PMCR- 2019/06/15 CRDT- 2018/09/23 06:00 PHST- 2018/02/22 00:00 [received] PHST- 2018/07/09 00:00 [revised] PHST- 2018/09/18 00:00 [accepted] PHST- 2018/09/23 06:00 [pubmed] PHST- 2019/10/08 06:00 [medline] PHST- 2018/09/23 06:00 [entrez] PHST- 2019/06/15 00:00 [pmc-release] AID - 0008-5472.CAN-18-0585 [pii] AID - 10.1158/0008-5472.CAN-18-0585 [doi] PST - ppublish SO - Cancer Res. 2018 Dec 15;78(24):6747-6761. doi: 10.1158/0008-5472.CAN-18-0585. Epub 2018 Sep 21.