Aspirin promotes RSL3-induced ferroptosis by suppressing mTOR/SREBP-1/SCD1-mediated lipogenesis in PIK3CA-mutatnt colorectal cancer

  • Redox Biol. 2022 Aug 4;55:102426. doi: 10.1016/j.redox.2022.102426.
Hao Chen  1 ,  Qinqin Qi  2 ,  Nan Wu  1 ,  Ying Wang  1 ,  Qian Feng  1 ,  Rong Jin  3 ,  Lei Jiang  4
Affiliations
  • 1. Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 2. Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 3. Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. Electronic address: [email protected].
  • 4. Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. Electronic address: [email protected].
PMID: 35963119 DOI: 10.1016/j.redox.2022.102426
Abstract

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 p110α 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.

Keywords
Aspirin; Colorectal cancer; Ferroptosis; SCD1; mTOR.
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