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

Francesca Ricciardiello; Yang Gang; Roberta Palorini; Quanxiao Li; Marco Giampà; Fangyu Zhao; Lei You; Barbara La Ferla; Humberto De Vitto; Wenfang Guan; Jin Gu; Taiping Zhang; Yupei Zhao; Ferdinando Chiaradonna

doi:10.1038/s41388-020-1260-1

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

Francesca Ricciardiello, Yang Gang, Roberta Palorini, Quanxiao Li, Marco Giampà, Fangyu Zhao, Lei You, Barbara La Ferla, Humberto De Vitto, Wenfang Guan, Jin Gu, Taiping Zhang, Yupei Zhao, Ferdinando Chiaradonna

Hormel Institute

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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.

Original language	English (US)
Pages (from-to)	4103-4117
Number of pages	15
Journal	Oncogene
Volume	39
Issue number	20
DOIs	https://doi.org/10.1038/s41388-020-1260-1
State	Published - May 14 2020

Bibliographical note

Funding Information:
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 indi-viduale 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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© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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Ricciardiello, F., Gang, Y., Palorini, R., Li, Q., Giampà, M., Zhao, F., You, L., La Ferla, B., De Vitto, H., Guan, W., Gu, J., Zhang, T., Zhao, Y., & Chiaradonna, F. (2020). Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation. Oncogene, 39(20), 4103-4117. https://doi.org/10.1038/s41388-020-1260-1

Ricciardiello, F, Gang, Y, Palorini, R, Li, Q, Giampà, M, Zhao, F, You, L, La Ferla, B, De Vitto, H, Guan, W, Gu, J, Zhang, T, Zhao, Y & Chiaradonna, F 2020, 'Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation', Oncogene, vol. 39, no. 20, pp. 4103-4117. https://doi.org/10.1038/s41388-020-1260-1

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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.",

author = "Francesca Ricciardiello and Yang Gang and Roberta Palorini and Quanxiao Li and Marco Giamp{\`a} and Fangyu Zhao and Lei You and {La Ferla}, Barbara and {De Vitto}, Humberto and Wenfang Guan and Jin Gu and Taiping Zhang and Yupei Zhao and Ferdinando Chiaradonna",

note = "Funding Information: 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 indi-viduale 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. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

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AU - Giampà, Marco

AU - Zhao, Fangyu

AU - You, Lei

AU - La Ferla, Barbara

AU - De Vitto, Humberto

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AU - Gu, Jin

AU - Zhang, Taiping

AU - Zhao, Yupei

AU - Chiaradonna, Ferdinando

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

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