TRAP1 enhances Warburg metabolism through modulation of PFK1 expression/activity and favors resistance to EGFR inhibitors in human colorectal carcinomas

Abstract

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.

Redox proteome analysis of auranofin exposed ovarian cancer cells (A2780)

“…Our data suggested that C501 oxidation is a mediator of AF toxicity, and we found that C501S mutation decreased the cell sensitivity to AF treatment. As previously reported, TRAP1 C501 S -nitrosylation impacts its protein expression levels and ATPase activity, both important for TRAP1 role in regulating the Warburg effect and sensitivity to drugs [ 63 , 64 , 98 , 99 ]. Here, the observed decreased sensitivity of the TRAP1 C501S mutant to AF agrees with the effects of C501 S -nitrosylation shown in previous studies.…”

Regulation of mitochondrial complex III activity and assembly by TRAP1 in cancer cells

“…The effects of TRAP1 on mitochondrial respiration are still controversial: TRAP1 silencing increases oxygen consumption in SAOS-2 osteosarcoma cells, PEA1 ovarian cancer cells, HCT116 colorectal carcinoma cells and mouse fibroblasts [ 7 , 8 , 17 , 18 ]; however, TRAP1 silencing or treatment with the mitochondria-directed HSP90 inhibitor Gamitrinibs reduces oxygen consumption and ATP production in PC3 prostate cancer cells and in LN229 glioblastoma cells, although in the specific metabolic context of low glucose availability [ 9 ]. To shed light on this complex scenario, as a preliminary approach we first analyzed the response of TRAP1 knock-down cells to a decreased glucose availability through the monitoring of AMPK activation over time and identified a significant AMPK phosphorylation after 4 h of glucose withdrawal (referred to as "low glucose” hereafter), specifically in TRAP1-expressing cells (Additional file 1 : Fig.…”

On The Origin of Speciation

“…However, male sterility due to malfunction of the MMI system is indeed a loss for species preservation, and it seems that some kind of defense system coexists. Fmr1 is involved in spermatogenesis, axoneme synthesis, and the Warburg effect (Zhang et al, 2004;Maddalena et al, 2020), and its function is very similar to that of SPAG1, so it may control SPAG1-2 expression as an RNA-binding translational regulatory protein. If the SPAG1-2 / Eri15 axis runs out of control due to widespread loss of Fx-mir, it may be that the misexpressed FMRP suppresses the translation of SPAG1-2 mRNA.…”