Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):2473-8. doi: 10.1073/pnas.1421601112. Epub 2015 Feb 9.

Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma.

Author information

1
INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France;
2
INSERM, UMR911, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, F-13385 Marseille, France; Service de Chirurgie Digestive et Viscérale, F-13385 Marseille, France;
3
INSERM, U1069, Laboratoire Nutrition, Croissance et Cancer, Université François Rabelais, F-37032 Tours, France;
4
INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France; Service Hospitalier d'Anatomie et Cytologie Pathologiques Humaines, Assistance Publique-Hôpitaux de Marseille, F-13015 Marseille, France;
5
European Genomic Institute for Diabetes, FR 3508, Université Lille 2, INSERM, U1011, and Institut Pasteur de Lille, F-59019 Lille, France; and.
6
Molecular Endocrinology and Oncology Research Center, Quebec, QC, Canada G1V 4G2.
7
INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, and Université Aix-Marseille, F-13009 Marseille, France; sophie.vasseur@inserm.fr.

Abstract

The malignant progression of pancreatic ductal adenocarcinoma (PDAC) is accompanied by a profound desmoplasia, which forces proliferating tumor cells to metabolically adapt to this new microenvironment. We established the PDAC metabolic signature to highlight the main activated tumor metabolic pathways. Comparative transcriptomic analysis identified lipid-related metabolic pathways as being the most highly enriched in PDAC, compared with a normal pancreas. Our study revealed that lipoprotein metabolic processes, in particular cholesterol uptake, are drastically activated in the tumor. This process results in an increase in the amount of cholesterol and an overexpression of the low-density lipoprotein receptor (LDLR) in pancreatic tumor cells. These findings identify LDLR as a novel metabolic target to limit PDAC progression. Here, we demonstrate that shRNA silencing of LDLR, in pancreatic tumor cells, profoundly reduces uptake of cholesterol and alters its distribution, decreases tumor cell proliferation, and limits activation of ERK1/2 survival pathway. Moreover, blocking cholesterol uptake sensitizes cells to chemotherapeutic drugs and potentiates the effect of chemotherapy on PDAC regression. Clinically, high PDAC Ldlr expression is not restricted to a specific tumor stage but is correlated to a higher risk of disease recurrence. This study provides a precise overview of lipid metabolic pathways that are disturbed in PDAC. We also highlight the high dependence of pancreatic cancer cells upon cholesterol uptake, and identify LDLR as a promising metabolic target for combined therapy, to limit PDAC progression and disease patient relapse.

KEYWORDS:

LDLR; cholesterol; gemcitabine; metabolism; pancreatic cancer

PMID:
25675507
PMCID:
PMC4345573
DOI:
10.1073/pnas.1421601112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center