PMID- 37270169
OWN - NLM
STAT- MEDLINE
DCOM- 20230627
LR  - 20240102
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Linking)
VI  - 327
DP  - 2023 Aug 15
TI  - Inhibition of pyruvate carboxylase reverses metformin resistance by activating 
      AMPK in pancreatic cancer.
PG  - 121817
LID - S0024-3205(23)00451-4 [pii]
LID - 10.1016/j.lfs.2023.121817 [doi]
AB  - AIMS: Pyruvate carboxylase (PC) plays a key role in cancer cell metabolic 
      reprogramming. Whether metabolic reprogramming and PC are related in PDAC is 
      unclear. Here, the effect of PC expression on PDAC tumorigenesis and metabolic 
      reprogramming were evaluated. MATERIALS AND METHODS: PC protein expression in 
      PDAC and precancerous tissues was measured through immunohistochemistry. The 
      maximum standardized uptake (SUVmax) of (18)F-fluoro-2-deoxy-2-d-glucose 
      ((18)F-FDG) in PDAC patient PET/CT scans before surgical resection was 
      retrospectively determined. Stable PC-knockdown and PC-overexpressing cells were 
      established using lentiviruses, and PDAC progression was assessed in vivo and in 
      vitro. Lactate content, (18)F-FDG cell uptake rate, mitochondrial oxygen 
      consumption rate (OCR) and extracellular acidification rate (ECAR) were measured 
      in cells. RNA sequencing revealed and qPCR verified differentially expressed 
      genes (DEGs) after PC knockdown. The signaling pathways involved were determined 
      by Western blotting. KEY FINDINGS: PC was significantly upregulated in PDAC 
      tissues vs. precancerous tissues. A high SUVmax correlated with PC upregulation. 
      PC knockdown significantly inhibited PDAC progression. Lactate content, SUVmax, 
      and ECAR significantly decreased after PC knockdown. Peroxisome 
      proliferator-activated receptor gamma coactivator-one alpha (PGC-1alpha) was 
      upregulated after PC knockdown; and PGC1a expression promoted AMPK 
      phosphorylation to activate mitochondrial metabolism. Metformin significantly 
      inhibited mitochondrial respiration after PC knockdown, further activated AMPK 
      and downstream carnitine palmitoyltransferase 1A (CPT1A)-regulated fatty acid 
      oxidation (FAO), and inhibited PDAC cells progression. SIGNIFICANCE: PDAC cell 
      uptake of FDG was positively correlated with PC expression. PC promotes PDAC 
      glycolysis, and reducing PC expression can increase PGC1a expression, activate 
      AMPK, and restore metformin sensitivity.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Liu, Chang
AU  - Liu C
AD  - Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China.
FAU - Zhou, Xiang
AU  - Zhou X
AD  - Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China.
FAU - Ju, Huijun
AU  - Ju H
AD  - Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China. Electronic address: juhuijun@hotmail.com.
FAU - Zhang, Yifan
AU  - Zhang Y
AD  - Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University 
      School of Medicine, Shanghai, China. Electronic address: zyf11300@rjh.com.cn.
LA  - eng
PT  - Journal Article
DEP - 20230602
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 6.4.1.1 (Pyruvate Carboxylase)
RN  - 0 (Transcription Factors)
RN  - 0Z5B2CJX4D (Fluorodeoxyglucose F18)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
SB  - IM
MH  - Humans
MH  - *Metformin/pharmacology
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Pyruvate Carboxylase/metabolism
MH  - Transcription Factors/metabolism
MH  - Fluorodeoxyglucose F18
MH  - Positron Emission Tomography Computed Tomography
MH  - Retrospective Studies
MH  - *Pancreatic Neoplasms/drug therapy/genetics
MH  - *Precancerous Conditions
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 
      1-alpha/genetics/metabolism
OTO - NOTNLM
OT  - FDG uptake
OT  - Metformin
OT  - OXPHOS
OT  - PC
OT  - PDAC
OT  - PGC-1alpha
COIS- Declaration of competing interest The authors declare that they have no competing 
      interests.
EDAT- 2023/06/04 01:08
MHDA- 2023/06/27 06:42
CRDT- 2023/06/03 19:27
PHST- 2023/03/09 00:00 [received]
PHST- 2023/05/24 00:00 [revised]
PHST- 2023/05/24 00:00 [accepted]
PHST- 2023/06/27 06:42 [medline]
PHST- 2023/06/04 01:08 [pubmed]
PHST- 2023/06/03 19:27 [entrez]
AID - S0024-3205(23)00451-4 [pii]
AID - 10.1016/j.lfs.2023.121817 [doi]
PST - ppublish
SO  - Life Sci. 2023 Aug 15;327:121817. doi: 10.1016/j.lfs.2023.121817. Epub 2023 Jun 
      2.