PMID- 35963119
OWN - NLM
STAT- Publisher
LR  - 20231019
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 55
DP  - 2022 Sep
TI  - Aspirin promotes RSL3-induced ferroptosis by suppressing 
      mTOR/SREBP-1/SCD1-mediated lipogenesis in PIK3CA-mutant colorectal cancer.
PG  - 102426
LID - S2213-2317(22)00198-7 [pii]
LID - 10.1016/j.redox.2022.102426 [doi]
LID - 102426
AB  - Ferroptosis, a new form of regulated cell death triggered by the iron-dependent 
      peroxidation of phospholipids, is associated with cellular metabolism, redox 
      homeostasis, and various signaling pathways related to cancer. Aspirin is a 
      widely used non-steroidal anti-inflammatory drug (NSAID) and has been reported to 
      show therapeutic benefit in cancers harboring oncogenic PIK3CA, which encodes the 
      catalytic p110alpha subunit of phosphoinositide 3-kinase (PI3K). In this study, we 
      found that aspirin sensitized cancer cells harboring oncogenic activation of 
      PIK3CA to ferroptosis induction. Mechanistically, aspirin inhibited protein 
      kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, suppressed 
      downstream sterol regulatory element-binding protein 1 (SREBP-1) expression, and 
      attenuated stearoyl-CoA desaturase-1 (SCD1)-mediated lipogenesis of 
      monounsaturated fatty acids, thus promoting RSL3-induced ferroptosis in 
      colorectal cancer (CRC) cells. Moreover, genetic ablation of SREBP-1 or SCD1 
      conferred cancer cells greater sensitivity to ferroptosis induction. Conversely, 
      ectopic expression of SREBP-1 or SCD1 restored ferroptosis resistance in CRC 
      cells and abolished the effect of aspirin on RSL3-induced cytotoxicity. 
      Additionally, the synergistic effects of aspirin and RSL3 were confirmed in a 
      xenograft mouse model. The combined use of aspirin and RSL3 resulted in 
      significant tumor suppression. Our work demonstrated that aspirin enhanced the 
      cytotoxic effect of RSL3 in PIK3CA-mutant cancers, and the combination of aspirin 
      and ferroptosis inducer displayed promising therapeutic effects in cancer 
      treatment.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Chen, Hao
AU  - Chen H
AD  - Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical 
      University, Wenzhou, 325000, China.
FAU - Qi, Qinqin
AU  - Qi Q
AD  - Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, 
      Wenzhou, 325000, China.
FAU - Wu, Nan
AU  - Wu N
AD  - Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical 
      University, Wenzhou, 325000, China.
FAU - Wang, Ying
AU  - Wang Y
AD  - Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical 
      University, Wenzhou, 325000, China.
FAU - Feng, Qian
AU  - Feng Q
AD  - Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical 
      University, Wenzhou, 325000, China.
FAU - Jin, Rong
AU  - Jin R
AD  - Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical 
      University, Wenzhou, 325000, China. Electronic address: jinrongjrjr@163.com.
FAU - Jiang, Lei
AU  - Jiang L
AD  - Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, 
      Wenzhou, 325000, China. Electronic address: lei.jiang@wmu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20220804
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
SB  - IM
PMC - PMC9389304
OTO - NOTNLM
OT  - Aspirin
OT  - Colorectal cancer
OT  - Ferroptosis
OT  - SCD1
OT  - mTOR
COIS- The authors have no conflicts of interest to disclose. Fig. 7 is created using 
      Figdraw (www.figdraw.com).
EDAT- 2022/08/14 06:00
MHDA- 2022/08/14 06:00
PMCR- 2022/08/04
CRDT- 2022/08/13 18:22
PHST- 2022/04/29 00:00 [received]
PHST- 2022/07/29 00:00 [revised]
PHST- 2022/07/30 00:00 [accepted]
PHST- 2022/08/14 06:00 [pubmed]
PHST- 2022/08/14 06:00 [medline]
PHST- 2022/08/13 18:22 [entrez]
PHST- 2022/08/04 00:00 [pmc-release]
AID - S2213-2317(22)00198-7 [pii]
AID - 102426 [pii]
AID - 10.1016/j.redox.2022.102426 [doi]
PST - ppublish
SO  - Redox Biol. 2022 Sep;55:102426. doi: 10.1016/j.redox.2022.102426. Epub 2022 Aug 
      4.