Author, as appears in the article.: Valli A, Morotti M, Zois CE, Albers PK, Soga T, Feldinger K, Fischer R, Frejno M, McIntyre A, Bridges E, Haider S, Buffa FM, Baban D, Rodriguez M, Yanes O, Whittington HJ, Lake HA, Zervou S, Lygate CA, Kessler BM, Harris AL

Department: Enginyeria Electrònica, Elèctrica i Automàtica

URV's Author/s: Yanes Torrado, Óscar

Keywords: Resistance Proliferation Phenotype Pathway Oxygen Kinase Glucose-metabolism Family Expression Aldolase

Abstract: Hypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1α is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways. We analyzed pathways that allow cells to survive hypoxic stress in the absence of HIF1α, using the HCT116 colon cancer cell line with deleted HIF1α versus control. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, and proteomic analysis and integrated the results. These showed surprisingly that in three-dimensional growth, a key regulatory step of glycolysis is Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained in hypoxia through upregulation of GLUT14, not previously recognized in this role. Finally, there was a marked adaptation and change of phosphocreatine energy pathways, which made the cells susceptible to inhibition of creatine metabolism in hypoxic conditions. Overall, our studies show a complex adaptation to hypoxia that can bypass HIF1α, but it is targetable and it provides new insight into the key metabolic pathways involved in cancer growth. IMPLICATIONS: Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting.©2019 American Association for Cancer Research.

Thematic Areas: Oncology Odontología Molecular biology Medicine (all) Medicina iii Medicina ii Medicina i Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Cell biology Cancer research Biotecnología

licence for use: https://creativecommons.org/licenses/by/3.0/es/

ISSN: 1541-7786

Author's mail: oscar.yanes@urv.cat

Author identifier: 0000-0003-3695-7157

Record's date: 2023-07-31

Papper version: info:eu-repo/semantics/publishedVersion

Link to the original source: https://mcr-aacrjournals-org.sabidi.urv.cat/content/17/7/1531

Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/

Papper original source: Molecular Cancer Research. 17 (7): 1531-1544

APA: Valli A, Morotti M, Zois CE, Albers PK, Soga T, Feldinger K, Fischer R, Frejno M, McIntyre A, Bridges E, Haider S, Buffa FM, Baban D, Rodriguez M, Yan (2019). Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism. Molecular Cancer Research, 17(7), 1531-1544. DOI: 10.1158/1541-7786.MCR-18-0315

Article's DOI: 10.1158/1541-7786.MCR-18-0315

Entity: Universitat Rovira i Virgili

Journal publication year: 2019

Publication Type: Journal Publications