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

Oncogene volume 39, pages 4103–4117 (2020)Cite this article

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Abstract

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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Fig. 1: PGM3 is upregulated in GEM resistant PDXs and negatively correlated with prognosis in PC.
Fig. 2: PGM3 contributed proliferation, invasion, migration, chemoresistance in vitro and tumor growth in mice.
Fig. 3: Targeting PGM3 induces cell growth arrest and apoptosis.
Fig. 4: FR054 synergizes with GEM and suppresses in vitro and in vivo proliferation.
Fig. 5: FR054 induces a sustained activation of UPR.
Fig. 6: FR054 inhibits EGFR-Akt axis.
Fig. 7: IHC and HE staining of PANC-1 and PDX-5 xenograft tumors.

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Acknowledgements

FC was supported by grants from MAECI (Executive Programme of Scientific and Technological Cooperation Italy-China 2019–2021, #CN19GR03), from Associazione Italiana per la Ricerca sul Cancro (A.I.R.C., IG2014 Id.15364) and Fondo individuale FFABBR_NAT 2017 (MIUR, Italy). TZ was supported by grants from Key Projects of International Scientific and Technological Innovation Cooperation Between Chinese and Italian Governments (2018YFE0118600), from the National Natural Science Foundation of China (No. 81772639), from Natural Science Foundation of Beijing (No. 7192157) and CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2016-I2M-1-001). YZ was supported by grants from Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2018PT32014). FR is supported by fellowship from MIUR. RP and HDV were supported by fellowship from MIUR and National Brazilian Institution of Science (CAPES 9281-13-4), respectively. We thank Neil Campbell for English editing.

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Author notes

  1. Humberto De Vitto

    Present address: Hormel Institute, University of Minnesota, Austin, MN, 55912, USA

  2. These authors contributed equally: Francesca Ricciardiello, Yang Gang

Authors and Affiliations

  1. Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126, Milan, Italy

    Francesca Ricciardiello, Roberta Palorini, Marco Giampà, Barbara La Ferla, Humberto De Vitto & Ferdinando Chiaradonna

  2. Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China

    Yang Gang, Quanxiao Li, Fangyu Zhao, Lei You, Taiping Zhang & Yupei Zhao

  3. MOE Key Laboratory of Bioinformatics; Bioinformatics Division, Center for Synthetic and Systems Biology, BNRist; Department of Automation, Tsinghua University, 100084, Beijing, China

    Wenfang Guan & Jin Gu

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Ricciardiello, F., Gang, Y., Palorini, R. et al. Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation. Oncogene 39, 4103–4117 (2020). https://doi.org/10.1038/s41388-020-1260-1

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