Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation

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 lin...

Full description

Saved in:
Bibliographic Details
Published in:Oncogene 2020-05, Vol.39 (20), p.4103-4117
Main Authors: Ricciardiello, Francesca, Gang, Yang, Palorini, Roberta, Li, Quanxiao, Giampà, Marco, Zhao, Fangyu, You, Lei, La Ferla, Barbara, De Vitto, Humberto, Guan, Wenfang, Gu, Jin, Zhang, Taiping, Zhao, Yupei, Chiaradonna, Ferdinando
Format: Article
Language:English
Subjects:
AKT protein
Animals
Antimitotic agents
Antineoplastic agents
Cancer
Cell death
Cell Line, Tumor
Cell migration
Chemoresistance
Chemotherapy
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Enzymes
Epidermal growth factor
Epidermal growth factor receptors
ErbB Receptors - genetics
ErbB Receptors - metabolism
Gemcitabine
Glucose metabolism
Glycosylation
Hexosamines - genetics
Hexosamines - metabolism
Humans
Metabolic pathways
Metabolism
Mice
mRNA
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Phosphoacetylglucosamine mutase
Physiological aspects
Prevention
Protein folding
Proteins
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
RNA
Signal Transduction - drug effects
Signal Transduction - genetics
Unfolded Protein Response - drug effects
Unfolded Protein Response - genetics
Xenograft Model Antitumor Assays
Xenografts
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-020-1260-1