PMID- 35915609
OWN - NLM
STAT- MEDLINE
DCOM- 20221212
LR  - 20221212
IS  - 1942-0994 (Electronic)
IS  - 1942-0900 (Print)
IS  - 1942-0994 (Linking)
VI  - 2022
DP  - 2022
TI  - Vitamin C Sensitizes Pancreatic Cancer Cells to Erastin-Induced Ferroptosis by 
      Activating the AMPK/Nrf2/HMOX1 Pathway.
PG  - 5361241
LID - 10.1155/2022/5361241 [doi]
LID - 5361241
AB  - Ferroptosis is a type of regulated cell death that displays a promising 
      therapeutic pathway for drug-resistant tumor cells. However, some pancreatic 
      cancer (PC) cells are less sensitive to erastin-induced ferroptosis, and normal 
      pancreatic cells are susceptible to this newly discovered cell death. Therefore, 
      there is an urgent need to find drugs to enhance the sensitivity of these PC 
      cells to erastin while limiting side effects. Here, we found that the oxidized 
      form of vitamin C-dehydroascorbic acid (DHA) can be transported into PC cells 
      expressing high levels of GLUT1, resulting in ferroptosis. Moreover, 
      pharmacological vitamin C combined with erastin can synergistically induce 
      ferroptosis of PC cells involving glutathione (GSH) reduction and ferrous iron 
      accumulation while inhibiting the cytotoxicity of normal cells. Mechanistically, 
      as a direct system Xc(-) inhibitor, erastin can directly suppress the synthesis 
      of GSH, and the recycling of vitamin C and DHA is performed through GSH 
      consumption, which is denoted as the classical mode. Furthermore, oxidative 
      stress induced by erastin and vitamin C could enhance the expression of HMOX1 via 
      the AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 
      2 (NRF2) pathway to increase the labile iron level, which is named the 
      nonclassical mode. In vivo experiments showed that erastin and vitamin C can 
      significantly slow tumor growth in PC xenografts. In summary, the combination of 
      erastin and vitamin C exerts a synergistic effect of classical and nonclassical 
      modes to induce ferroptosis in PC cells, which may provide a promising 
      therapeutic strategy for PC.
CI  - Copyright (c) 2022 Yawen Liu et al.
FAU - Liu, Yawen
AU  - Liu Y
AUID- ORCID: 0000-0001-8544-5006
AD  - Department of Gastroenterology, Affiliated Hospital of Jiangsu University, 
      Jiangsu University, Zhenjiang, China 212001.
FAU - Huang, Pu
AU  - Huang P
AUID- ORCID: 0000-0001-5861-6295
AD  - Medical School of Chinese PLA, Beijing, China 100853.
AD  - Department of General Surgery, The First Medical Centre, Chinese PLA General 
      Hospital, Beijing, China 100853.
FAU - Li, Zheng
AU  - Li Z
AUID- ORCID: 0000-0002-7969-7490
AD  - Department of Gastroenterology, Affiliated Hospital of Jiangsu University, 
      Jiangsu University, Zhenjiang, China 212001.
FAU - Xu, Chunhui
AU  - Xu C
AUID- ORCID: 0000-0002-0469-8990
AD  - Department of Gastroenterology, Affiliated Hospital of Jiangsu University, 
      Jiangsu University, Zhenjiang, China 212001.
FAU - Wang, Huizhi
AU  - Wang H
AUID- ORCID: 0000-0002-0213-2248
AD  - Department of Gastroenterology, Affiliated Hospital of Jiangsu University, 
      Jiangsu University, Zhenjiang, China 212001.
FAU - Jia, Baoqing
AU  - Jia B
AUID- ORCID: 0000-0002-7006-0741
AD  - Department of General Surgery, The First Medical Centre, Chinese PLA General 
      Hospital, Beijing, China 100853.
FAU - Gong, Aihua
AU  - Gong A
AUID- ORCID: 0000-0001-8803-4595
AD  - Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, 
      China 212013.
FAU - Xu, Min
AU  - Xu M
AUID- ORCID: 0000-0002-5587-5520
AD  - Department of Gastroenterology, Affiliated Hospital of Jiangsu University, 
      Jiangsu University, Zhenjiang, China 212001.
LA  - eng
PT  - Journal Article
DEP - 20220719
PL  - United States
TA  - Oxid Med Cell Longev
JT  - Oxidative medicine and cellular longevity
JID - 101479826
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - PQ6CK8PD0R (Ascorbic Acid)
RN  - 0 (erastin)
RN  - GAN16C9B8O (Glutathione)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 1.14.14.18 (HMOX1 protein, human)
RN  - E1UOL152H7 (Iron)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NRF1 protein, human)
RN  - 0 (Nuclear Respiratory Factor 1)
RN  - 0 (Piperazines)
SB  - IM
MH  - Humans
MH  - AMP-Activated Protein Kinases
MH  - Ascorbic Acid/pharmacology
MH  - *Ferroptosis
MH  - Glutathione/metabolism
MH  - Heme Oxygenase-1
MH  - Iron/metabolism
MH  - NF-E2-Related Factor 2
MH  - Nuclear Respiratory Factor 1
MH  - *Pancreatic Neoplasms/drug therapy
MH  - Piperazines
PMC - PMC9338737
COIS- The authors declare no conflicts of interest.
EDAT- 2022/08/03 06:00
MHDA- 2022/08/04 06:00
PMCR- 2022/07/19
CRDT- 2022/08/02 01:44
PHST- 2022/01/06 00:00 [received]
PHST- 2022/04/04 00:00 [revised]
PHST- 2022/05/17 00:00 [accepted]
PHST- 2022/08/02 01:44 [entrez]
PHST- 2022/08/03 06:00 [pubmed]
PHST- 2022/08/04 06:00 [medline]
PHST- 2022/07/19 00:00 [pmc-release]
AID - 10.1155/2022/5361241 [doi]
PST - epublish
SO  - Oxid Med Cell Longev. 2022 Jul 19;2022:5361241. doi: 10.1155/2022/5361241. 
      eCollection 2022.