1. Selective PI3Kδ inhibitor TYM-3-98 suppresses AKT/mTOR/SREBP1-mediated lipogenesis and promotes ferroptosis in KRAS-mutant colorectal cancer.
- Author
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Zheng YN, Lou SY, Lu J, Zheng FL, Tang YM, Zhang EJ, Cui SL, and Zhao HJ
- Subjects
- 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, 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
- Abstract
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).)
- Published
- 2024
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