دورية أكاديمية
Selective PI3Kδ inhibitor TYM-3-98 suppresses AKT/mTOR/SREBP1-mediated lipogenesis and promotes ferroptosis in KRAS-mutant colorectal cancer.
العنوان: | Selective PI3Kδ inhibitor TYM-3-98 suppresses AKT/mTOR/SREBP1-mediated lipogenesis and promotes ferroptosis in KRAS-mutant colorectal cancer. |
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المؤلفون: | Zheng YN; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China., Lou SY; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.; Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China., Lu J; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China., Zheng FL; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China., Tang YM; Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China., Zhang EJ; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China., Cui SL; Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. slcui@zju.edu.cn., Zhao HJ; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China. zhj@zcmu.edu.cn.; Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China. zhj@zcmu.edu.cn. |
المصدر: | Cell death & disease [Cell Death Dis] 2024 Jul 03; Vol. 15 (7), pp. 474. Date of Electronic Publication: 2024 Jul 03. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: London : Nature Pub. Group |
مواضيع طبية MeSH: | Ferroptosis*/drug effects , Ferroptosis*/genetics , Colorectal Neoplasms*/metabolism , Colorectal Neoplasms*/pathology , Colorectal Neoplasms*/drug therapy , Colorectal Neoplasms*/genetics , TOR Serine-Threonine Kinases*/metabolism , Proto-Oncogene Proteins c-akt*/metabolism , Sterol Regulatory Element Binding Protein 1*/metabolism , Sterol Regulatory Element Binding Protein 1*/genetics , Lipogenesis*/drug effects , Lipogenesis*/genetics , Proto-Oncogene Proteins p21(ras)*/metabolism , Proto-Oncogene Proteins p21(ras)*/genetics , Signal Transduction*/drug effects, Humans ; Animals ; Mice ; Mice, Nude ; Cell Line, Tumor ; Mutation/genetics ; Xenograft Model Antitumor Assays ; Mice, Inbred BALB C ; Class I Phosphatidylinositol 3-Kinases/metabolism ; Class I Phosphatidylinositol 3-Kinases/genetics ; Phosphoinositide-3 Kinase Inhibitors/pharmacology |
مستخلص: | Colorectal cancer (CRC) is one of the most common tumors of the digestive system worldwide. KRAS mutations limit the use of anti-EGFR antibodies in combination with chemotherapy for the treatment of CRC. Therefore, novel targeted therapies are needed to overcome the KRAS-induced oncogenesis. Recent evidence suggests that inhibition of PI3K led to ferroptosis, a nonapoptotic cell death closely related to KRAS-mutant cells. Here, we showed that a selective PI3Kδ inhibitor TYM-3-98 can suppress the AKT/mTOR signaling and activate the ferroptosis pathway in KRAS-mutant CRC cells in a concentration-dependent manner. This was evidenced by the lipid peroxidation, iron accumulation, and depletion of GSH. Moreover, the overexpression of the sterol regulatory element-binding protein 1 (SREBP1), a downstream transcription factor regulating lipid metabolism, conferred CRC cells greater resistance to ferroptosis induced by TYM-3-98. In addition, the effect of TYM-3-98 was confirmed in a xenograft mouse model, which demonstrated significant tumor suppression without obvious hepatoxicity or renal toxicity. Taken together, our work demonstrated that the induction of ferroptosis contributed to the PI3Kδ inhibitor-induced cell death via the suppression of AKT/mTOR/SREBP1-mediated lipogenesis, thus displaying a promising therapeutic effect of TYM-3-98 in CRC treatment. (© 2024. The Author(s).) |
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المشرفين على المادة: | EC 2.7.11.1 (TOR Serine-Threonine Kinases) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) 0 (Sterol Regulatory Element Binding Protein 1) EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) EC 2.7.1.1 (MTOR protein, human) 0 (KRAS protein, human) 0 (SREBF1 protein, human) EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) 0 (Phosphoinositide-3 Kinase Inhibitors) |
تواريخ الأحداث: | Date Created: 20240702 Date Completed: 20240702 Latest Revision: 20240725 |
رمز التحديث: | 20240726 |
مُعرف محوري في PubMed: | PMC11220027 |
DOI: | 10.1038/s41419-024-06848-7 |
PMID: | 38956060 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2041-4889 |
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DOI: | 10.1038/s41419-024-06848-7 |