Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation.
Animals
Cell Line, Tumor
Deoxycytidine
/ analogs & derivatives
Drug Resistance, Neoplasm
/ drug effects
ErbB Receptors
/ genetics
Hexosamines
/ genetics
Humans
Mice
Pancreatic Neoplasms
/ drug therapy
Proto-Oncogene Proteins c-akt
/ genetics
Signal Transduction
/ drug effects
Unfolded Protein Response
/ drug effects
Xenograft Model Antitumor Assays
Gemcitabine
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
12
10
2019
accepted:
05
03
2020
revised:
04
03
2020
pubmed:
3
4
2020
medline:
25
11
2020
entrez:
3
4
2020
Statut:
ppublish
Résumé
Different evidence has indicated metabolic rewiring as a necessity for pancreatic cancer (PC) growth, invasion, and chemotherapy resistance. A relevant role has been assigned to glucose metabolism. In particular, an enhanced flux through the Hexosamine Biosynthetic Pathway (HBP) has been tightly linked to PC development. Here, we show that enhancement of the HBP, through the upregulation of the enzyme Phosphoacetylglucosamine Mutase 3 (PGM3), is associated with the onset of gemcitabine (GEM) resistance in PC. Indeed, mRNA profiles of GEM sensitive and resistant patient-derived tumor xenografts (PDXs) indicate that PGM3 expression is specifically increased in GEM-resistant PDXs. Of note, PGM3 results also overexpressed in human PC tissues as compared to paired adjacent normal tissues and its higher expression in PC patients is associated with worse median overall survival (OS). Strikingly, genetic or pharmacological PGM3 inhibition reduces PC cell growth, migration, invasion, in vivo tumor growth and enhances GEM sensitivity. Thus, combined treatment between a specific inhibitor of PGM3, named FR054, and GEM results in a potent reduction of xenograft tumor growth without any obvious side effects in normal tissues. Mechanistically, PGM3 inhibition, reducing protein glycosylation, causes a sustained Unfolded Protein Response (UPR), a significant attenuation of the pro-tumorigenic Epidermal Growth Factor Receptor (EGFR)-Akt axis, and finally cell death. In conclusion this study identifies the HBP as a metabolic pathway involved in GEM resistance and provides a strong rationale for a PC therapy addressing the combined treatment with the PGM3 inhibitor and GEM.
Identifiants
pubmed: 32235891
doi: 10.1038/s41388-020-1260-1
pii: 10.1038/s41388-020-1260-1
doi:
Substances chimiques
Hexosamines
0
Deoxycytidine
0W860991D6
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Gemcitabine
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4103-4117Références
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