دورية أكاديمية
أعرض في EDS

Selective PI3Kδ inhibitor TYM-3-98 suppresses AKT/mTOR/SREBP1-mediated lipogenesis and promotes ferroptosis in KRAS-mutant colorectal cancer.

التفاصيل البيبلوغرافية
العنوان: Selective PI3Kδ inhibitor TYM-3-98 suppresses AKT/mTOR/SREBP1-mediated lipogenesis and promotes ferroptosis in KRAS-mutant colorectal cancer.
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).)
References: Cancer Sci. 2020 Sep;111(9):3142-3154. (PMID: 32536012)
Lancet. 2019 Oct 19;394(10207):1467-1480. (PMID: 31631858)
J Exp Clin Cancer Res. 2021 Oct 18;40(1):328. (PMID: 34663410)
Int J Mol Sci. 2021 Mar 27;22(7):. (PMID: 33801659)
Bioengineered. 2022 Feb;13(2):2498-2512. (PMID: 35067161)
Eur J Cancer. 2012 Jan;48(1):149-57. (PMID: 22079609)
Clin Cancer Res. 2008 Feb 15;14(4):1172-81. (PMID: 18281552)
Nat Rev Clin Oncol. 2021 May;18(5):280-296. (PMID: 33514910)
Int J Mol Sci. 2019 Jan 18;20(2):. (PMID: 30669372)
Leukemia. 2017 Jun;31(6):1423-1433. (PMID: 27843137)
CA Cancer J Clin. 2022 Sep;72(5):409-436. (PMID: 35736631)
Oncologist. 2022 Dec 9;27(12):1025-1033. (PMID: 36124727)
Cell Chem Biol. 2019 Mar 21;26(3):420-432.e9. (PMID: 30686757)
Clin Cancer Res. 2014 Apr 1;20(7):1803-13. (PMID: 24523440)
Life Sci. 2024 Jun 15;347:122662. (PMID: 38670450)
Drug Saf. 2019 Feb;42(2):247-262. (PMID: 30649751)
Redox Biol. 2022 Sep;55:102426. (PMID: 35963119)
Biomed Pharmacother. 2023 Feb;158:114102. (PMID: 36528917)
Cancer Discov. 2019 Apr;9(4):482-491. (PMID: 30867161)
Cancer Med. 2016 Feb;5(2):248-55. (PMID: 26715098)
Cancer Res. 2003 Apr 1;63(7):1667-75. (PMID: 12670921)
Pharmacol Res. 2021 Jun;168:105579. (PMID: 33774181)
Cancer Sci. 2021 Sep;112(9):3895-3910. (PMID: 34185934)
Cell Death Dis. 2021 Mar 17;12(4):289. (PMID: 33731703)
J Pathol Clin Res. 2023 Sep;9(5):423-435. (PMID: 37147883)
Cancer Med. 2013 Aug;2(4):496-506. (PMID: 24156022)
Trends Cell Biol. 2023 Mar;33(3):185-188. (PMID: 36473802)
Med Res Rev. 2015 Jul;35(4):720-52. (PMID: 25763934)
Blood. 2021 Jul 8;138(1):44-56. (PMID: 33684943)
Biomed Pharmacother. 2022 Sep;153:113524. (PMID: 36076606)
Cancer Sci. 2019 Mar;110(3):997-1011. (PMID: 30618098)
Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31189-31197. (PMID: 33229547)
Semin Cancer Biol. 2019 Dec;59:125-132. (PMID: 31323288)
J Cell Biochem. 2018 Mar;119(3):2460-2469. (PMID: 28230287)
Signal Transduct Target Ther. 2021 Dec 16;6(1):425. (PMID: 34916492)
Oncol Rep. 2018 Aug;40(2):1083-1092. (PMID: 29845289)
Sci Signal. 2020 Jan 07;13(613):. (PMID: 31911433)
J Cell Physiol. 2022 Mar;237(3):1720-1752. (PMID: 34897682)
J Exp Clin Cancer Res. 2021 Apr 26;40(1):141. (PMID: 33902658)
Phytomedicine. 2022 Jul;101:154143. (PMID: 35537248)
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
الوصف
تدمد:2041-4889
DOI:10.1038/s41419-024-06848-7