Open AccessTRAP1 enhances Warburg metabolism through modulation of PFK1 expression/activity and favors resistance to EGFR inhibitors in human colorectal carcinomas
Author(s) -
Maddalena Francesca,
Condelli Valentina,
Matassa Danilo Swann,
Pacelli Consiglia,
Scrima Rosella,
Lettini Giacomo,
Li Bergolis Valeria,
Pietrafesa Michele,
Crispo Fabiana,
Piscazzi Annamaria,
Storto Giovanni,
Capitanio Nazzareno,
Esposito Franca,
Landriscina Matteo
Publication year - 2020
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12814
Subject(s) - downregulation and upregulation , cetuximab , warburg effect , glycolysis , glut1 , anaerobic glycolysis , cancer research , chemistry , oxidative phosphorylation , microbiology and biotechnology , biology , colorectal cancer , biochemistry , metabolism , glucose uptake , cancer , endocrinology , genetics , insulin , gene
Here, we show that TRAP1 modulates glycolytic metabolism by regulating PFK1 activity/stability. In a high TRAP1 background, TRAP1 inhibits cellular respiration and interacts with PFK1 on the ER and this enables PFK1 glycolytic activity preventing its ubiquitination/degradation. In a low TRAP1 background, cellular respiration is upregulated and PFK1 activity reduced due to increased ubiquitination/degradation and this results in loss of TRAP1 control on glycolytic cascade. The increased levels of citrate, observed in conditions of enhanced cellular respiration, are responsible for the inhibition of PFK1 activity, and this results in enhancement of PFK1 ubiquitination/degradation.