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Combining metabolic phenotype determination with metabolomics and transcriptional analyses to reveal pathways regulated by hydroxycarboxylic acid receptor 2

Rabe, Philipp and Gehmlich, Mareike and Peters, Anna and Krumbholz, Petra and Nordström, Anders and Staeubert, Claudia (2022). Combining metabolic phenotype determination with metabolomics and transcriptional analyses to reveal pathways regulated by hydroxycarboxylic acid receptor 2. Discover Oncology. 13 , 47
[Research article]

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Abstract

Background The adaptation of cellular metabolism is considered a hallmark of cancer. Oncogenic signaling pathways support tumorigenesis and cancer progression through the induction of certain metabolic phenotypes associated with altered regulation of key metabolic enzymes. Hydroxycarboxylic acid receptor 2 (HCA(2)) is a G protein-coupled receptor previously shown to act as a tumor suppressor. Here, we aimed to unveil the connection between cellular metabolism and HCA(2) in BT-474 cells. Moreover, we intend to clarify how well this metabolic phenotype is reflected in transcriptional changes and metabolite levels as determined by global metabolomics analyses. Methods We performed both, siRNA mediated knockdown of HCA(2) and stimulation with the HCA(2)-specific agonist monomethyl fumarate. Seahorse technology was used to determine the role of HCA(2) in BT-474 breast cancer cell metabolism and its potential to induce a switch in the metabolic phenotype in the presence of different energy substrates. Changes in the mRNA expression of metabolic enzymes were detected with real-time quantitative PCR (RT-qPCR). Untargeted liquid chromatography-mass spectrometry (LC-MS) metabolic profiling was used to determine changes in metabolite levels. Results Knockdown or stimulation of HCA(2) induced changes in the metabolic phenotype of BT474 cells dependent on the availability of energy substrates. The presence of HCA(2) was associated with increased glycolytic flux with no fatty acids available. This was reflected in the increased mRNA expression of the glycolytic enzymes PFKFB4 and PKM2, which are known to promote the Warburg effect and have been described as prognostic markers in different types of cancer. With exogenous palmitate present, HCA(2) caused elevated fatty acid oxidation and likely lipolysis. The increase in lipolysis was also detectable at the transcriptional level of ATGL and the metabolite levels of palmitic and stearic acid. Conclusions We combined metabolic phenotype determination with metabolomics and transcriptional analyses and identified HCA(2) as a regulator of glycolytic flux and fatty acid metabolism in BT-474 breast cancer cells. Thus, HCA(2), for which agonists are already widely used to treat diseases such as psoriasis or hyperlipidemia, may prove useful as a target in combination cancer therapy.

Authors/Creators:Rabe, Philipp and Gehmlich, Mareike and Peters, Anna and Krumbholz, Petra and Nordström, Anders and Staeubert, Claudia
Title:Combining metabolic phenotype determination with metabolomics and transcriptional analyses to reveal pathways regulated by hydroxycarboxylic acid receptor 2
Series Name/Journal:Discover Oncology
Year of publishing :2022
Volume:13
Article number:47
Number of Pages:13
Publisher:SPRINGER
ISSN:1868-8497
Language:English
Publication Type:Research article
Article category:Scientific peer reviewed
Version:Published version
Copyright:Creative Commons: Attribution 4.0
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 302 Clinical Medicine > Cancer and Oncology
Keywords:Metabolite-sensing GPCR, Cancer metabolism, Metabolite profile, LC-MS, HCA(2), GPR109A
URN:NBN:urn:nbn:se:slu:epsilon-p-118023
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-118023
Additional ID:
Type of IDID
DOI10.1007/s12672-022-00503-3
Web of Science (WoS)000810671200001
ID Code:28610
Faculty:S - Faculty of Forest Sciences
Department:(S) > Dept. of Forest Genetics and Plant Physiology
Deposited By: SLUpub Connector
Deposited On:26 Aug 2022 12:04
Metadata Last Modified:26 Aug 2022 12:11

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