期刊
ONCOGENE
卷 39, 期 20, 页码 4103-4117出版社
SPRINGERNATURE
DOI: 10.1038/s41388-020-1260-1
关键词
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资金
- MAECI (Executive Programme of Scientific and Technological Cooperation Italy-China) [CN19GR03]
- Associazione Italiana per la Ricerca sul Cancro [15364]
- Fondo individuale FFABBR_NAT 2017 (MIUR, Italy)
- Chinese Government [2018YFE0118600]
- National Natural Science Foundation of China [81772639]
- Natural Science Foundation of Beijing [7192157]
- CAMS Innovation Fund for Medical Sciences (CIFMS) [2016-I2M-1-001]
- Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2018PT32014]
- MIUR
- National Brazilian Institution of Science (CAPES) [9281-13-4]
- Italian Government [2018YFE0118600]
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.
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