MAPK14/p38α-dependent modulation of glucose metabolism affects ROS levels and autophagy during starvation

Enrico Desideri, Rolando Vegliante, Simone Cardaci, Ridvan Nepravishta, Maurizio Paci, Maria Rosa Ciriolo

Research output: Contribution to journalArticlepeer-review

Abstract

Increased glycolytic flux is a common feature of many cancer cells, which have adapted their metabolism to maximize glucose incorporation and catabolism to generate ATP and substrates for biosynthetic reactions. Indeed, glycolysis allows a rapid production of ATP and provides metabolic intermediates required for cancer cells growth. Moreover, it makes cancer cells less sensitive to fluctuations of oxygen tension, a condition usually occurring in a newly established tumor environment. Here, we provide evidence for a dual role of MAPK14 in driving a rearrangement of glucose metabolism that contributes to limiting reactive oxygen species (ROS) production and autophagy activation in condition of nutrient deprivation. We demonstrate that MAPK14 is phosphoactivated during nutrient deprivation and affects glucose metabolism at 2 different levels: on the one hand, it increases SLC2A3 mRNA and protein levels, resulting in a higher incorporation of glucose within the cell. This event involves the MAPK14-mediated enhancement of HI F1A protein stability. On the other hand, MAPK14 mediates a metabolic shift from glycolysis to the pentose phosphate pathway (PPP) through the modulation of PFKFB3 (6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase 3) degradation by the proteasome. This event requires the presence of 2 distinct degradation sequences, KEN box and DSG motif Ser273, which are recognized by 2 different E3 ligase complexes. The mutation of either motif increases PFKFB3 resistance to starvation-induced degradation. The MAPK14-driven metabolic reprogramming sustains the production of NADPH, an important cofactor for many reduction reactions and for the maintenance of the proper intracellular redox environment, resulting in reduced levels of ROS. The final effect is a reduced activation of autophagy and an increased resistance to nutrient deprivation.

Original languageEnglish
Pages (from-to)1652-1665
Number of pages14
JournalAutophagy
Volume10
Issue number9
DOIs
Publication statusPublished - Sep 1 2014

Keywords

  • Autophagy
  • Cell death
  • Glycolysis
  • HIF1A
  • MAPK14
  • PFKFB3
  • PPP

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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