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

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.

SUBMITTER: Chen H

PROVIDER: S-EPMC9389304 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

Chen Hao H Qi Qinqin Q Wu Nan N Wang Ying Y Feng Qian Q Jin Rong R Jiang Lei L

Redox biology 20220804

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 sensi ...[more]

PMID: 35963119

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Project description:BackgroundRegular use of aspirin after a diagnosis of colon cancer has been associated with a superior clinical outcome. Experimental evidence suggests that inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) (also known as cyclooxygenase-2) by aspirin down-regulates phosphatidylinositol 3-kinase (PI3K) signaling activity. We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene) might differ from the effect among those with wild-type PIK3CA cancers.MethodsWe obtained data on 964 patients with rectal or colon cancer from the Nurses' Health Study and the Health Professionals Follow-up Study, including data on aspirin use after diagnosis and the presence or absence of PIK3CA mutation. We used a Cox proportional-hazards model to compute the multivariate hazard ratio for death. We examined tumor markers, including PTGS2, phosphorylated AKT, KRAS, BRAF, microsatellite instability, CpG island methylator phenotype, and methylation of long interspersed nucleotide element 1.ResultsAmong patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with superior colorectal cancer-specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P<0.001 by the log-rank test) and overall survival (multivariate hazard ratio for death from any cause, 0.54; 95% CI, 0.31 to 0.94; P=0.01 by the log-rank test). In contrast, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not associated with colorectal cancer-specific survival (multivariate hazard ratio, 0.96; 95% CI, 0.69 to 1.32; P=0.76 by the log-rank test; P=0.009 for interaction between aspirin and PIK3CA variables) or overall survival (multivariate hazard ratio, 0.94; 95% CI, 0.75 to 1.17; P=0.96 by the log-rank test; P=0.07 for interaction).ConclusionsRegular use of aspirin after diagnosis was associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. The findings from this molecular pathological epidemiology study suggest that the PIK3CA mutation in colorectal cancer may serve as a predictive molecular biomarker for adjuvant aspirin therapy. (Funded by The National Institutes of Health and others.).

Dataset Information

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

Publications

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

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