Key regulator PNPLA8 drives phospholipid reprogramming induced proliferation and migration in triple-negative breast cancer.

Humans Cell Line, Tumor Cell Movement / genetics Cell Proliferation / genetics Phenotype Phosphatidylinositol 3-Kinases / genetics Phospholipids / therapeutic use Triple Negative Breast Neoplasms / pathology
Breast cancer Eicosanoids Invasion Metabolism reprogramming Migration PNPLA8 Phospholipid Proliferation Triple negative

Journal

Breast cancer research : BCR
ISSN: 1465-542X
Titre abrégé: Breast Cancer Res
Pays: England
ID NLM: 100927353

Informations de publication

Date de publication:
28 Nov 2023
Historique:
received: 19 01 2023
accepted: 06 11 2023
medline: 30 11 2023
pubmed: 29 11 2023
entrez: 29 11 2023
Statut: epublish

Résumé

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and leads to the poorest patient outcomes despite surgery and chemotherapy treatment. Exploring new molecular mechanisms of TNBC that could lead to the development of novel molecular targets are critically important for improving therapeutic options for treating TNBC. We sought to identify novel therapeutic targets in TNBC by combining genomic and functional studies with lipidomic analysis, which included mechanistic studies to elucidate the pathways that tie lipid profile to critical cancer cell properties. Our studies were performed in a large panel of human breast cancer cell lines and patient samples. Comprehensive lipid profiling revealed that phospholipid metabolism is reprogrammed in TNBC cells. We discovered that patatin-like phospholipase domain-containing lipase 8 (PNPLA8) is overexpressed in TNBC cell lines and tissues from breast cancer patients. Silencing of PNPLA8 disrupted phospholipid metabolic reprogramming in TNBC, particularly affecting the levels of phosphatidylglycerol (PG), phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and glycerophosphocholine (GPC). We showed that PNPLA8 is essential in regulating cell viability, migration and antioxidation in TNBC cells and promoted arachidonic acid and eicosanoid production, which in turn activated PI3K/Akt/Gsk3β and MAPK signaling. Our study highlights PNPLA8 as key regulator of phospholipid metabolic reprogramming and malignant phenotypes in TNBC, which could be further developed as a novel molecular treatment target.

Sections du résumé

BACKGROUND BACKGROUND
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and leads to the poorest patient outcomes despite surgery and chemotherapy treatment. Exploring new molecular mechanisms of TNBC that could lead to the development of novel molecular targets are critically important for improving therapeutic options for treating TNBC.
METHODS METHODS
We sought to identify novel therapeutic targets in TNBC by combining genomic and functional studies with lipidomic analysis, which included mechanistic studies to elucidate the pathways that tie lipid profile to critical cancer cell properties. Our studies were performed in a large panel of human breast cancer cell lines and patient samples.
RESULTS RESULTS
Comprehensive lipid profiling revealed that phospholipid metabolism is reprogrammed in TNBC cells. We discovered that patatin-like phospholipase domain-containing lipase 8 (PNPLA8) is overexpressed in TNBC cell lines and tissues from breast cancer patients. Silencing of PNPLA8 disrupted phospholipid metabolic reprogramming in TNBC, particularly affecting the levels of phosphatidylglycerol (PG), phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and glycerophosphocholine (GPC). We showed that PNPLA8 is essential in regulating cell viability, migration and antioxidation in TNBC cells and promoted arachidonic acid and eicosanoid production, which in turn activated PI3K/Akt/Gsk3β and MAPK signaling.
CONCLUSIONS CONCLUSIONS
Our study highlights PNPLA8 as key regulator of phospholipid metabolic reprogramming and malignant phenotypes in TNBC, which could be further developed as a novel molecular treatment target.

Identifiants

DOI: 10.1186/s13058-023-01742-0 PMID: 38017485 PMC: PMC10683240
pubmed: 38017485
doi: 10.1186/s13058-023-01742-0
pii: 10.1186/s13058-023-01742-0
pmc: PMC10683240
doi:

Substances chimiques

Phosphatidylinositol 3-Kinases EC 2.7.1.-
Phospholipids 0
PLA2G6 protein, human EC 3.1.1.4

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

148

Subventions

Organisme : NIH HHS
ID : P30 MH075673
Pays : United States
Organisme : NIH HHS
ID : R01 CA213428
Pays : United States

Informations de copyright

© 2023. The Author(s).

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Auteurs

Zheqiong Tan (Z)

Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Pragney Deme (P)

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Keerti Boyapati (K)

Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Britt S R Claes (BSR)

Maastricht MultiModal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands.

Annet A M Duivenvoorden (AAM)

Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.

Ron M A Heeren (RMA)

Maastricht MultiModal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands.

Caitlin M Tressler (CM)

Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Norman James Haughey (NJ)

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Kristine Glunde (K)

Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. kglunde@mri.jhu.edu.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. kglunde@mri.jhu.edu.
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. kglunde@mri.jhu.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Key regulator PNPLA8 drives phospholipid...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Key regulator PNPLA8 drives phospholipid...
questionsmedicales.fr › Phénomènes physiologiques › Mouvement cellulaire › Key regulator PNPLA8 drives phospholipid...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Key regulator PNPLA8 drives phospholipid...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Key regulator PNPLA8 drives phospholipid...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Key regulator PNPLA8 drives phospholipid...
questionsmedicales.fr › Lipides › Lipides membranaires › Phospholipides › Key regulator PNPLA8 drives phospholipid...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Tumeurs du sein triple-négatives › Key regulator PNPLA8 drives phospholipid...