PMID- 36384580
OWN - NLM
STAT- MEDLINE
DCOM- 20221121
LR  - 20221121
IS  - 1476-511X (Electronic)
IS  - 1476-511X (Linking)
VI  - 21
IP  - 1
DP  - 2022 Nov 16
TI  - WY-14643 attenuates lipid deposition via activation of the PPARalpha/CPT1A axis by 
      targeting Gly335 to inhibit cell proliferation and migration in ccRCC.
PG  - 121
LID - 10.1186/s12944-022-01726-7 [doi]
LID - 121
AB  - BACKGROUND: Histologically, cytoplasmic deposits of lipids and glycogen are 
      common in clear cell renal cell carcinoma (ccRCC). Owing to the significance of 
      lipid deposition in ccRCC, numerous trials targeting lipid metabolism have shown 
      certain therapeutic potential. The agonism of peroxisome proliferator-activated 
      receptor-alpha (PPARalpha) via ligands, including WY-14,643, has been considered a 
      promising intervention for cancers. METHODS: First, the effects of WY-14,643 on 
      malignant behaviors were investigated in ccRCC in vitro. After RNA sequencing, 
      the changes in lipid metabolism, especially neutral lipids and glycerol, were 
      further evaluated. Finally, the underlying mechanisms were revealed. RESULTS: 
      Phenotypically, the proliferation and migration of ccRCC cells treated with 
      WY-14,643 were significantly inhibited in vitro. A theoretical functional 
      mechanism was proposed in ccRCC: WY-14,643 mediates lipid consumption by 
      recognizing carnitine palmitoyltransferase 1 A (CPT1A). Activation of PPARalpha using 
      WY-14,643 reduces lipid deposition by increasing the CPT1A level, which also 
      suppresses the NF-kappaB signaling pathway. Spatially, WY-14,643 binds and activates 
      PPARalpha by targeting Gly335. CONCLUSION: Overall, WY-14,643 suppresses the 
      biological behaviors of ccRCC in terms of cell proliferation, migration, and cell 
      cycle arrest. Furthermore, its anticancer properties are mediated by the 
      inhibition of lipid accumulation, at least in part, through the PPARalpha/CPT1A axis 
      by targeting Gly335, as part of the process, NF-kappaB signaling is also suppressed. 
      Pharmacological activation of PPARalpha might offer a new treatment option for ccRCC.
CI  - (c) 2022. The Author(s).
FAU - Wang, Rui
AU  - Wang R
AD  - Department of Urology, The First Affiliated Hospital of Dalian Medical 
      University, Dalian, China.
FAU - Zhao, Jun
AU  - Zhao J
AD  - Department of Urology, The Third People's Hospital of Chengdu, Chengdu, China.
FAU - Jin, Jiacheng
AU  - Jin J
AD  - Department of Urology, The First Affiliated Hospital of Dalian Medical 
      University, Dalian, China.
FAU - Tian, Yun
AU  - Tian Y
AD  - Department of Urology, The First Affiliated Hospital of Dalian Medical 
      University, Dalian, China.
FAU - Lan, Lan
AU  - Lan L
AD  - Department of Urology, The First Affiliated Hospital of Dalian Medical 
      University, Dalian, China.
FAU - Wang, Xuejian
AU  - Wang X
AD  - Department of Urology, The First Affiliated Hospital of Dalian Medical 
      University, Dalian, China.
FAU - Zhu, Liang
AU  - Zhu L
AD  - College of Basic Medical Science, Dalian Medical University, Dalian, China. 
      zhuliang0210@sina.com.
FAU - Wang, Jianbo
AU  - Wang J
AD  - Department of Urology, The First Affiliated Hospital of Dalian Medical 
      University, Dalian, China. wangjianbo@dmu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20221116
PL  - England
TA  - Lipids Health Dis
JT  - Lipids in health and disease
JID - 101147696
RN  - 0 (PPAR alpha)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - 86C4MRT55A (pirinixic acid)
RN  - 0 (NF-kappa B)
RN  - 0 (Lipids)
SB  - IM
MH  - Humans
MH  - PPAR alpha/genetics/metabolism
MH  - Carnitine O-Palmitoyltransferase/genetics
MH  - *Carcinoma, Renal Cell/drug therapy/genetics
MH  - NF-kappa B
MH  - Cell Proliferation
MH  - *Kidney Neoplasms
MH  - Lipids
PMC - PMC9667690
OTO - NOTNLM
OT  - CPT1A
OT  - Lipid accumulation
OT  - PPARalpha
OT  - WY-14643
OT  - ccRCC
COIS- The authors declare no conflicts of interest.
EDAT- 2022/11/18 06:00
MHDA- 2022/11/22 06:00
PMCR- 2022/11/16
CRDT- 2022/11/17 09:51
PHST- 2022/09/07 00:00 [received]
PHST- 2022/10/19 00:00 [accepted]
PHST- 2022/11/17 09:51 [entrez]
PHST- 2022/11/18 06:00 [pubmed]
PHST- 2022/11/22 06:00 [medline]
PHST- 2022/11/16 00:00 [pmc-release]
AID - 10.1186/s12944-022-01726-7 [pii]
AID - 1726 [pii]
AID - 10.1186/s12944-022-01726-7 [doi]
PST - epublish
SO  - Lipids Health Dis. 2022 Nov 16;21(1):121. doi: 10.1186/s12944-022-01726-7.