PMID- 35223522
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220301
IS  - 2234-943X (Print)
IS  - 2234-943X (Electronic)
IS  - 2234-943X (Linking)
VI  - 12
DP  - 2022
TI  - Decrease of Intracellular Glutamine by STF-62247 Results in the Accumulation of 
      Lipid Droplets in von Hippel-Lindau Deficient Cells.
PG  - 841054
LID - 10.3389/fonc.2022.841054 [doi]
LID - 841054
AB  - Kidney cancer is one of the top ten cancer diagnosed worldwide and its incidence 
      has increased the last 20 years. Clear Cell Renal Cell Carcinoma (ccRCC) are 
      characterized by mutations that inactivate the von Hippel-Lindau (VHL) tumor 
      suppressor gene and evidence indicated alterations in metabolic pathways, 
      particularly in glutamine metabolism. We previously identified a small molecule, 
      STF-62247, which target VHL-deficient renal tumors by affecting late-stages of 
      autophagy and lysosomal signaling. In this study, we investigated ccRCC 
      metabolism in VHL-deficient and proficient cells exposed to the small molecule. 
      Metabolomics profiling using 1H NMR demonstrated that STF-62247 increases levels 
      of glucose, pyruvate, glycerol 3-phosphate while glutamate, asparagine, and 
      glutathione significantly decreased. Diminution of glutamate and glutamine was 
      further investigated using mass spectrometry, western blot analyses, enzymatic 
      activities, and viability assays. We found that expression of SLC1A5 increases in 
      VHL-deficient cells treated with STF-62247, possibly to stimulate glutamine 
      uptake intracellularly to counteract the diminution of this amino acid. However, 
      exogenous addition of glutamine was not able to rescue cell viability induced by 
      the small molecule. Instead, our results showed that VHL-deficient cells utilize 
      glutamine to produce fatty acid in response to STF-62247. Surprisingly, this 
      occurs through oxidative phosphorylation in STF-treated cells while control cells 
      use reductive carboxylation to sustain lipogenesis. We also demonstrated that 
      STF-62247 stimulated expression of stearoyl-CoA desaturase (SCD1) and peripilin2 
      (PLIN2) to generate accumulation of lipid droplets in VHL-deficient cells. 
      Moreover, the carnitine palmitoyltransferase 1A (CPT1A), which control the entry 
      of fatty acid into mitochondria for beta-oxidation, also increased in response to 
      STF-62247. CPT1A overexpression in ccRCC is known to limit tumor growth. 
      Together, our results demonstrated that STF-62247 modulates cellular metabolism 
      of glutamine, an amino acid involved in the autophagy-lysosome process, to 
      support lipogenesis, which could be implicated in the signaling driving to cell 
      death.
CI  - Copyright (c) 2022 Johnson, Nowlan, Sahin, Barnett, Joy, Touaibia, Cuperlovic-Culf, 
      Zofija Avizonis and Turcotte.
FAU - Johnson, Mathieu
AU  - Johnson M
AD  - Department of Chemistry and Biochemistry, Universite de Moncton, Moncton, NB, 
      Canada.
AD  - Atlantic Cancer Research Institute, Moncton, NB, Canada.
FAU - Nowlan, Sarah
AU  - Nowlan S
AD  - Department of Chemistry and Biochemistry, Universite de Moncton, Moncton, NB, 
      Canada.
AD  - Atlantic Cancer Research Institute, Moncton, NB, Canada.
FAU - Sahin, Gulsum
AU  - Sahin G
AD  - Department of Chemistry and Biochemistry, Universite de Moncton, Moncton, NB, 
      Canada.
AD  - Atlantic Cancer Research Institute, Moncton, NB, Canada.
FAU - Barnett, David A
AU  - Barnett DA
AD  - Atlantic Cancer Research Institute, Moncton, NB, Canada.
FAU - Joy, Andrew P
AU  - Joy AP
AD  - Atlantic Cancer Research Institute, Moncton, NB, Canada.
FAU - Touaibia, Mohamed
AU  - Touaibia M
AD  - Department of Chemistry and Biochemistry, Universite de Moncton, Moncton, NB, 
      Canada.
FAU - Cuperlovic-Culf, Miroslava
AU  - Cuperlovic-Culf M
AD  - National Research Council of Canada, Digital Technologies Research Center, 
      Ottawa, ON, Canada.
FAU - Zofija Avizonis, Daina
AU  - Zofija Avizonis D
AD  - Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
FAU - Turcotte, Sandra
AU  - Turcotte S
AD  - Department of Chemistry and Biochemistry, Universite de Moncton, Moncton, NB, 
      Canada.
AD  - Atlantic Cancer Research Institute, Moncton, NB, Canada.
LA  - eng
PT  - Journal Article
DEP - 20220209
PL  - Switzerland
TA  - Front Oncol
JT  - Frontiers in oncology
JID - 101568867
PMC - PMC8865074
OTO - NOTNLM
OT  - CCRCC kidney cancer
OT  - cancer
OT  - fatty acid
OT  - glutamine (Gln)
OT  - lipid droplet (LD)
OT  - metabolomics
OT  - von Hippel - Lindau
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/03/01 06:00
MHDA- 2022/03/01 06:01
PMCR- 2022/01/01
CRDT- 2022/02/28 05:38
PHST- 2021/12/21 00:00 [received]
PHST- 2022/01/13 00:00 [accepted]
PHST- 2022/02/28 05:38 [entrez]
PHST- 2022/03/01 06:00 [pubmed]
PHST- 2022/03/01 06:01 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fonc.2022.841054 [doi]
PST - epublish
SO  - Front Oncol. 2022 Feb 9;12:841054. doi: 10.3389/fonc.2022.841054. eCollection 
      2022.