PMID- 38029544
OWN - NLM
STAT- MEDLINE
DCOM- 20240103
LR  - 20240106
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 691
DP  - 2024 Jan 8
TI  - Fatty acid elongation regulates mitochondrial beta-oxidation and cell viability in 
      prostate cancer by controlling malonyl-CoA levels.
PG  - 149273
LID - S0006-291X(23)01367-0 [pii]
LID - 10.1016/j.bbrc.2023.149273 [doi]
AB  - Recently, the fatty acid elongation enzyme ELOVL5 was identified as a critical 
      pro-metastatic factor in prostate cancer, required for cell growth and 
      mitochondrial homeostasis. The fatty acid elongation reaction catalyzed by ELOVL5 
      utilizes malonyl-CoA as the carbon donor. Here, we demonstrate that ELOVL5 
      knockdown causes malonyl-CoA accumulation. Malonyl-CoA is a cellular substrate 
      that can inhibit fatty acid beta-oxidation in the mitochondria through allosteric 
      inhibition of carnitine palmitoyltransferase 1A (CPT1A), the enzyme that controls 
      the rate-limiting step of the long chain fatty acid beta-oxidation cycle. We 
      hypothesized that changes in malonyl-CoA abundance following ELOVL5 knockdown 
      could influence mitochondrial beta-oxidation rates in prostate cancer cells, and 
      regulate cell viability. Accordingly, we find that ELOVL5 knockdown is associated 
      with decreased mitochondrial beta-oxidation in prostate cancer cells. Combining 
      ELOVL5 knockdown with FASN inhibition to increase malonyl-CoA abundance 
      endogenously enhances the effect of ELOVL5 knockdown on prostate cancer cell 
      viability, while preventing malonyl-CoA production rescues the cells from the 
      effect of ELOVL5 knockdown. Our findings indicate an additional role for fatty 
      acid elongation, in the control of malonyl-CoA homeostasis, alongside its 
      established role in the production of long-chain fatty acid species, to explain 
      the importance of fatty acid elongation for cell viability.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Scott, Julia S
AU  - Scott JS
AD  - South Australian ImmunoGENomics Cancer Institute, Adelaide Medical School and 
      Freemasons Centre for Male Health and Wellbeing, University of Adelaide, 
      Adelaide, SA, 5005, Australia; Precision Cancer Medicine Theme, South Australian 
      Health and Medical Research Institute, Adelaide, SA, 5000, Australia.
FAU - Quek, Lake-Ee
AU  - Quek LE
AD  - School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, 
      2006, Australia.
FAU - Hoy, Andrew J
AU  - Hoy AJ
AD  - School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and 
      Health, The University of Sydney, Sydney, NSW, 2006, Australia.
FAU - Swinnen, Johannes V
AU  - Swinnen JV
AD  - LKI - Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid 
      Metabolism and Cancer, KU Leuven, Leuven, B-3000, Belgium.
FAU - Nassar, Zeyad D
AU  - Nassar ZD
AD  - South Australian ImmunoGENomics Cancer Institute, Adelaide Medical School and 
      Freemasons Centre for Male Health and Wellbeing, University of Adelaide, 
      Adelaide, SA, 5005, Australia; Precision Cancer Medicine Theme, South Australian 
      Health and Medical Research Institute, Adelaide, SA, 5000, Australia.
FAU - Butler, Lisa M
AU  - Butler LM
AD  - South Australian ImmunoGENomics Cancer Institute, Adelaide Medical School and 
      Freemasons Centre for Male Health and Wellbeing, University of Adelaide, 
      Adelaide, SA, 5005, Australia; Precision Cancer Medicine Theme, South Australian 
      Health and Medical Research Institute, Adelaide, SA, 5000, Australia. Electronic 
      address: lisa.butler@adelaide.edu.au.
LA  - eng
PT  - Journal Article
DEP - 20231118
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 524-14-1 (Malonyl Coenzyme A)
RN  - 0 (Fatty Acids)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
SB  - IM
MH  - Male
MH  - Humans
MH  - *Malonyl Coenzyme A/metabolism/pharmacology
MH  - Cell Survival
MH  - Fatty Acids/metabolism
MH  - Mitochondria/metabolism
MH  - Oxidation-Reduction
MH  - *Prostatic Neoplasms/genetics/metabolism
MH  - Carnitine O-Palmitoyltransferase/metabolism
OTO - NOTNLM
OT  - Fatty acid elongation
OT  - Fatty acid oxidation
OT  - Malonyl-CoA
OT  - Prostate cancer
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/11/30 00:41
MHDA- 2024/01/03 09:42
CRDT- 2023/11/29 18:06
PHST- 2023/11/03 00:00 [received]
PHST- 2023/11/15 00:00 [accepted]
PHST- 2024/01/03 09:42 [medline]
PHST- 2023/11/30 00:41 [pubmed]
PHST- 2023/11/29 18:06 [entrez]
AID - S0006-291X(23)01367-0 [pii]
AID - 10.1016/j.bbrc.2023.149273 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2024 Jan 8;691:149273. doi: 
      10.1016/j.bbrc.2023.149273. Epub 2023 Nov 18.