CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis

Penfold, Lucy; Woods, Angela; Muckett, Phillip; Nikitin, Alexander Yu.; Kent, Tera R.; Zhang, Shuai; Graham, Rosalind; Pollard, Alice; Carling, David

doi:10.1158/0008-5472.can-18-0585

Cited by 58 publications

(62 citation statements)

References 55 publications

(80 reference statements)

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“…6a). Although there is evidence suggesting that AMPK might help cancer cells survive under certain circumstances 25 , there is more support in the literature for the notion that AMPK acts as a tumor suppressor by leading to cell growth inhibition and cell cycle arrest [26][27][28][29] . In particular, AMPK activation has proven to be an effective strategy to inhibit pancreatic cancer cell growth [30][31][32] .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway

et al. 2019

Cell Death Dis

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Pancreatic cancer is a highly malignant cancer and lacks effective therapeutic targets. Protein-tyrosine phosphatase 1B (PTP1B), a validated therapeutic target for diabetes and obesity, also plays a critical positive or negative role in tumorigenesis. However, the role of PTP1B in pancreatic cancer remains elusive. Here, we initially demonstrated that PTP1B was highly expressed in pancreatic tumors, and was positively correlated with distant metastasis and tumor staging, and indicated poor survival. Then, inhibition of PTP1B either by shRNA or by a specific small-molecule inhibitor significantly suppressed pancreatic cancer cell growth, migration and colony formation with cell cycle arrest in vitro and inhibited pancreatic cancer progression in vivo. Mechanism studies revealed that PTP1B targeted the PKM2/ AMPK/mTOC1 signaling pathway to regulate cell growth. PTP1B inhibition directly increased PKM2 Tyr-105 phosphorylation to further result in significant activation of AMPK, which decreased mTOC1 activity and led to inhibition of p70S6K. Meanwhile, the decreased phosphorylation of PRAS40 caused by decreased PKM2 activity also helped to inhibit mTOC1. Collectively, these findings support the notion of PTP1B as an oncogene and a promising therapeutic target for PDAC.

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Section: Discussionmentioning

confidence: 99%

Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway

et al. 2019

Cell Death Dis

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“…This was paralleled by an increase of AR peaks in the gene bodies and upstream of the transcription start point, as exempli ed for CAMKK2, HMGCR and PFKFB2. CAMKK2 activates AMPK and reduces downstream lipogenesis, but also directly stimulates lipogenesis in an AMPK-independent way [25]. HMGCR plays an essential role in cholesterol biosynthesis and its overexpression has been linked to enzalutamide resistance [40], possibly due to elevated intracrine androgen synthesis [41].…”

Section: Discussionmentioning

confidence: 99%

“…Activated AMPK induces autophagy, promotes mitochondrial biogenesis and is involved in apoptosis [18,20,21], thereby fostering prostate cancer growth and survival, whereas silencing AMPK expression reduces prostate cancer cell proliferation and migration [13,22]. However, other studies report that AMPK has a tumor suppressor role in prostate cancer [19,[23][24][25], so that potent and selective chemical probes [26] will be essential to understand the enigmatic function of AMPK in cancer and other pathologies [2,3,9,12]. AMPK activators mainly bind to the allosteric drug and metabolite site located at the α/β subunit interface and have different isoform selectivity [11].…”

Section: Introductionmentioning

confidence: 99%

“…An inhibitory impact of these compounds on the proliferation of prostate cancer models has been reported but in several cases promiscuous or weak activators were used, which makes interpretation di cult [5,11,12]. Data with more selective compounds such as MT 63-78 or 991 also suggest a role of AMPK in impairing prostate cancer cell proliferation, via reduction of lipogenesis and independently of CaMMK2 [24,25]. A phase 1 clinical study focusing on advanced tumors was initiated with the AMPK activator ASP4132 already several years ago, but only few preclinical data have been reported for this compound [27].…”

Section: Introductionmentioning

confidence: 99%

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The Potent and Selective AMPK Inhibitor BAY-3827 Shows Strong Efficacy in Androgen-Dependent Prostate Cancer Models

Lemos

Schulze

Baumgart

et al. 2020

Preprint

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Background: 5´ adenosine monophosphate-activated kinase (AMPK) is an essential regulator of cellular energy homeostasis which has been associated with different pathologies, including cancer. Precisely defining the role of AMPK in these processes necessitates the availability of a potent and selective inhibitor.Methods: High-throughput screening and subsequent chemical optimization led to the identification of the selective inhibitor BAY-3827. Cell proliferation and mechanistic assays, as well as gene expression analysis and chromatin immunoprecipitation were used to investigate the cellular impact of BAY-3827 and the crosstalk between lipid metabolism and androgen signaling in prostate cancer models. Also, fatty acid turnover was determined by examining lipid droplet formation.Results: BAY-3827 prevented phosphorylation of acetyl-CoA carboxylase 1 and showed strongest anti-proliferative activity in androgen-dependent prostate cancer cell lines. Analysis of genes involved in AMPK signaling revealed that the expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), fatty acid synthase (FASN) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), all of which are involved in lipid metabolism, was strongly upregulated by androgen in responsive prostate cancer cell lines. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis identified androgen receptor (AR) binding peaks in these genes. BAY-3827 strongly down-regulated the expression of lipase E (LIPE), cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B) and serine-threonine kinase AKT3 in the responsive prostate cancer cell lines. Also, the expression of members of the carnitine palmitoyl-transferase 1 (CPT1) family was inhibited by BAY-3827, and this was paralleled by impaired lipid flux.Conclusions: The availability of the potent and selective inhibitor BAY-3827 will contribute to a better understanding of the biological role of AMPK signaling in cancer, especially in prostate adenocarcinoma.

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“…PCa is well recognized as a lipid-enriched tumor, and an important biological feature of its progression is the dysregulation of lipid metabolism [3][4][5]. Previous studies indicate that inhibiting de novo lipogenesis via selectively deleting calcium/calmodulin-dependent protein kinase kinase 2, activating AMP-activated protein kinase, or inhibiting fatty acid synthase (FASN), reduced cell growth in human PCa cells [6,7].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of lipogenesis and induction of apoptosis by valproic acid in prostate cancer cells via the C/EBPα/SREBP-1 pathway

Pang

Zhang

Yuan

et al. 2020

Preprint

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Background: Lipid metabolism reprogramming is now accepted as a new hallmark of cancer. Hence, targeting the lipogenesis pathway may be a potential avenue for cancer treatment. Valproic acid (VPA) emerges as a promising drug for cancer therapy, however, the underlying mechanisms are not yet fully understood. This study aimed to investigate the effects and mechanisms of VPA on cell viability, lipogenesis, and apoptosis in human prostate cancer PC-3 cells. Methods: The effects of VPA on the viability and migration of PC-3 cells were investigated using MTT cell viability assay and wound-healing assay. Oil-Red O staining was used to examine lipid droplets, and DAPI staining assay and Annexin V-FITC and PI double-staining assay were used to measure the extent of cell apoptosis. Quantitative real-time PCR and Western blotting were used to determine the expression of lipogenesis and apoptosis genes. Statistical and analytical data were analyzed with SPSS 17.0 Software, and statistical significance was set to * P < 0.05, ** P < 0.01, and *** P < 0.001 levels. Results: The results showed that VPA significantly reduced lipid accumulation and induced apoptosis of PC-3 cells. Moreover, the expression of CCAAT/enhancer-binding protein α (C/EBPα), as well as sterol regulatory element binding protein 1 (SREBP-1) and its downstream effectors, including fatty acid synthase (FASN), acetyl CoA carboxylase 1 (ACC1), and antiapoptotic B cell lymphoma 2 (Bcl-2), markedly decreased in PC-3 cells after VPA administration. Mechanistically, the overexpression of C/EBPα rescued the levels of SREBP-1, FASN, ACC1, and Bcl-2, enhanced lipid accumulation and attenuated apoptosis of VPA-treated PC-3 cells. Conversely, knockdown of C/EBPα by siRNA further decreased lipid accumulation, enhanced apoptosis, and reduced the levels of SREBP-1, FASN, ACC1, and Bcl-2. In addition, SREBP-1a and 1c enhanced the expression of FASN and ACC1, but only SREBP-1a had a signiﬁcant eﬀect on Bcl-2 expression in VPA-treated PC-3 cells.Conclusions: On the whole, it is concluded that VPA significantly inhibits cell viability via decreasing lipogenesis and inducing apoptosis via the C/EBPα/SREBP-1 pathway in PC-3 cells. Therefore VPA which targets lipid metabolism and apoptosis is a promising candidate for prostate cancer chemotherapy.

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CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis

Cited by 58 publications

References 55 publications

Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway

Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway

The Potent and Selective AMPK Inhibitor BAY-3827 Shows Strong Efficacy in Androgen-Dependent Prostate Cancer Models

Inhibition of lipogenesis and induction of apoptosis by valproic acid in prostate cancer cells via the C/EBPα/SREBP-1 pathway

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