The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models

by Selleckchem | Sep 24 2023

Purpose: 5' adenosine monophosphate-activated kinase (AMPK) is an essential regulator of cellular energy homeostasis and has been associated with different pathologies, including cancer. Precisely defining the biological role of AMPK necessitates the availability of a potent and selective inhibitor.

Methods: High-throughput screening and chemical optimization were performed to identify a novel AMPK inhibitor. Cell proliferation and mechanistic assays, as well as gene expression analysis and chromatin immunoprecipitation were used to investigate the cellular impact as well as the crosstalk between lipid metabolism and androgen signaling in prostate cancer models. Also, fatty acid turnover was determined by examining lipid droplet formation.

Results: We identified BAY-3827 as a novel and potent AMPK inhibitor with additional activity against ribosomal 6 kinase (RSK) family members. It displays strong anti-proliferative effects in androgen-dependent prostate cancer cell lines. Analysis of genes involved in AMPK signaling revealed that the expression of those encoding 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 models. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis identified several androgen receptor (AR) binding peaks in the HMGCR and PFKFB2 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 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 inhibitor BAY-3827 will contribute to a better understanding of the role of AMPK signaling in cancer, especially in prostate cancer.

Comments:

The research described in the provided text focuses on the identification and characterization of a novel and potent inhibitor of 5' adenosine monophosphate-activated kinase (AMPK), called BAY-3827. AMPK is a crucial regulator of cellular energy balance, and dysregulation of this pathway has been associated with various diseases, including cancer.

To identify the inhibitor, the researchers employed high-throughput screening and chemical optimization techniques. BAY-3827 was found to not only inhibit AMPK but also exhibit activity against ribosomal 6 kinase (RSK) family members. The compound was then tested in prostate cancer cell lines, specifically those that are dependent on androgen signaling for their growth.

The results showed that BAY-3827 exerted strong anti-proliferative effects in androgen-dependent prostate cancer cells. The researchers further investigated the cellular impact of the inhibitor and explored the interplay between lipid metabolism and androgen signaling in these cancer models. They analyzed the expression of genes involved in AMPK signaling and identified upregulation of genes related to lipid metabolism, including 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), fatty acid synthase (FASN), and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), in response to androgen stimulation. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis revealed binding sites of the androgen receptor (AR) in the HMGCR and PFKFB2 genes.

Moreover, BAY-3827 was found to downregulate the expression of lipase E (LIPE), cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B), and serine-threonine kinase AKT3 in responsive prostate cancer cells. The inhibitor also inhibited the expression of members of the carnitine palmitoyl-transferase 1 (CPT1) family, which are involved in lipid flux.

Overall, the discovery of the potent AMPK inhibitor BAY-3827 contributes to a better understanding of the role of AMPK signaling in cancer, particularly in prostate cancer. The inhibitor's effects on lipid metabolism and androgen signaling provide insights into the mechanisms underlying cancer progression and highlight potential therapeutic targets for further investigation.