PMID- 33218188
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220716
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 12
IP  - 11
DP  - 2020 Nov 18
TI  - CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and 
      Promotes Antioxidant Defenses in Prostate Cancer.
LID - 10.3390/cancers12113431 [doi]
LID - 3431
AB  - Cancers reprogram their metabolism to adapt to environmental changes. In this 
      study, we examined the consequences of altered expression of the mitochondrial 
      enzyme carnitine palmitoyl transferase I (CPT1A) in prostate cancer (PCa) cell 
      models. Using transcriptomic and metabolomic analyses, we compared LNCaP-C4-2 
      cell lines with depleted (knockdown (KD)) or increased (overexpression (OE)) 
      CPT1A expression. Mitochondrial reactive oxygen species (ROS) were also measured. 
      Transcriptomic analysis identified ER stress, serine biosynthesis and lipid 
      catabolism as significantly upregulated pathways in the OE versus KD cells. On 
      the other hand, androgen response was significantly downregulated in OE cells. 
      These changes associated with increased acyl-carnitines, serine synthesis and 
      glutathione precursors in OE cells. Unexpectedly, OE cells showed increased 
      mitochondrial ROS but when challenged with fatty acids and no androgens, the 
      Superoxide dismutase 2 (SOD2) enzyme increased in the OE cells, suggesting better 
      antioxidant defenses with excess CPT1A expression. Public databases also showed 
      decreased androgen response correlation with increased serine-related metabolism 
      in advanced PCa. Lastly, worse progression free survival was observed with 
      increased lipid catabolism and decreased androgen response. Excess CPT1A is 
      associated with a ROS-mediated stress phenotype that can support PCa disease 
      progression. This study provides a rationale for targeting lipid catabolic 
      pathways for therapy in hormonal cancers.
FAU - Joshi, Molishree
AU  - Joshi M
AD  - Department of Pharmacology, University of Colorado Anschutz Medical Campus, 
      Aurora, CO 80045, USA.
FAU - Kim, Jihye
AU  - Kim J
AD  - Division of Medical Oncology, University of Colorado Anschutz Medical Campus, 
      Aurora, CO 80045, USA.
FAU - D'Alessandro, Angelo
AU  - D'Alessandro A
AUID- ORCID: 0000-0002-2258-6490
AD  - Department of Biochemistry, University of Colorado Anschutz Medical Campus, 
      Aurora, CO 80045, USA.
AD  - University of Colorado Comprehensive Cancer Center, University of Colorado 
      Anschutz Medical Campus, Aurora, CO 80045, USA.
FAU - Monk, Emily
AU  - Monk E
AUID- ORCID: 0000-0003-1037-4172
AD  - Division of Medical Oncology, University of Colorado Anschutz Medical Campus, 
      Aurora, CO 80045, USA.
FAU - Bruce, Kimberley
AU  - Bruce K
AD  - Division of Endocrinology, Metabolism and Diabetes, University of Colorado 
      Anschutz Medical Campus, Aurora, CO 80045, USA.
FAU - Elajaili, Hanan
AU  - Elajaili H
AD  - Department of Pediatrics Critical Care, University of Colorado Anschutz Medical 
      Campus, Aurora, CO 80045, USA.
FAU - Nozik-Grayck, Eva
AU  - Nozik-Grayck E
AD  - Department of Pediatrics Critical Care, University of Colorado Anschutz Medical 
      Campus, Aurora, CO 80045, USA.
FAU - Goodspeed, Andrew
AU  - Goodspeed A
AD  - Department of Pharmacology, University of Colorado Anschutz Medical Campus, 
      Aurora, CO 80045, USA.
AD  - University of Colorado Comprehensive Cancer Center, University of Colorado 
      Anschutz Medical Campus, Aurora, CO 80045, USA.
FAU - Costello, James C
AU  - Costello JC
AD  - Department of Pharmacology, University of Colorado Anschutz Medical Campus, 
      Aurora, CO 80045, USA.
AD  - University of Colorado Comprehensive Cancer Center, University of Colorado 
      Anschutz Medical Campus, Aurora, CO 80045, USA.
FAU - Schlaepfer, Isabel R
AU  - Schlaepfer IR
AUID- ORCID: 0000-0002-8659-9629
AD  - Division of Medical Oncology, University of Colorado Anschutz Medical Campus, 
      Aurora, CO 80045, USA.
LA  - eng
GR  - R35 HL139726/HL/NHLBI NIH HHS/United States
GR  - U01 CA231978/CA/NCI NIH HHS/United States
GR  - Sept2020/Nutrition and Obesity Research Center/
GR  - P30 CA046934/CA/NCI NIH HHS/United States
GR  - AWD-193286/Cancer League of Colorado/
GR  - 129846-RSG-16-256/American Cancer Society/
GR  - P30CA046934 and CA231978/NH/NIH HHS/United States
PT  - Journal Article
DEP - 20201118
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC7709014
OTO - NOTNLM
OT  - CPT1A
OT  - ROS
OT  - androgen response
OT  - fatty acids
OT  - oxidative stress
OT  - prostate cancer
OT  - serine
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript, or in the decision to publish the results.
EDAT- 2020/11/22 06:00
MHDA- 2020/11/22 06:01
PMCR- 2020/11/18
CRDT- 2020/11/21 01:01
PHST- 2020/10/06 00:00 [received]
PHST- 2020/11/03 00:00 [revised]
PHST- 2020/11/09 00:00 [accepted]
PHST- 2020/11/21 01:01 [entrez]
PHST- 2020/11/22 06:00 [pubmed]
PHST- 2020/11/22 06:01 [medline]
PHST- 2020/11/18 00:00 [pmc-release]
AID - cancers12113431 [pii]
AID - cancers-12-03431 [pii]
AID - 10.3390/cancers12113431 [doi]
PST - epublish
SO  - Cancers (Basel). 2020 Nov 18;12(11):3431. doi: 10.3390/cancers12113431.