Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma.

IF 11.7 1区 医学 Q1 CELL BIOLOGY Cell Reports Medicine Pub Date : 2024-09-17 Epub Date: 2024-09-04 DOI:10.1016/j.xcrm.2024.101706
Yaogang Zhong, Feng Geng, Logan Mazik, Xinmin Yin, Aline Paixao Becker, Shabber Mohammed, Huali Su, Enming Xing, Yongjun Kou, Cheng-Yao Chiang, Yunzhou Fan, Yongchen Guo, Qiang Wang, Pui-Kai Li, Xiaokui Mo, Etienne Lefai, Liqing He, Xiaolin Cheng, Xiang Zhang, Arnab Chakravarti, Deliang Guo
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Abstract

Antipsychotic drugs have been shown to have antitumor effects but have had limited potency in the clinic. Here, we unveil that pimozide inhibits lysosome hydrolytic function to suppress fatty acid and cholesterol release in glioblastoma (GBM), the most lethal brain tumor. Unexpectedly, GBM develops resistance to pimozide by boosting glutamine consumption and lipogenesis. These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo. Our findings underscore the promising therapeutic potential of effectively targeting GBM by combining glutamine metabolism inhibition with lysosome suppression.

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针对谷氨酰胺代谢和溶酶体脂质代谢的组合疗法可有效抑制胶质母细胞瘤。
抗精神病药物已被证明具有抗肿瘤作用,但在临床上的效力有限。在这里,我们揭示了匹莫齐特能抑制溶酶体水解功能,从而抑制胶质母细胞瘤(GBM)这一最致命脑肿瘤中脂肪酸和胆固醇的释放。意想不到的是,胶质母细胞瘤通过增加谷氨酰胺消耗和脂肪生成对匹莫齐特产生抗性。我们发现,SREBP-1 会上调谷氨酰胺转运体 ASCT2 的表达。谷氨酰胺反过来又会通过释放氨来加强SREBP-1的激活,从而形成一个前馈循环,放大谷氨酰胺代谢和脂质合成,导致耐药性。通过药理学靶向 ASCT2 或谷氨酰胺酶,结合匹莫齐特(pimozide)来破坏这一循环,可诱导显著的线粒体损伤和氧化应激,导致体外和体内的 GBM 细胞死亡。我们的研究结果凸显了通过将谷氨酰胺代谢抑制与溶酶体抑制相结合来有效靶向 GBM 的治疗潜力。
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来源期刊
Cell Reports Medicine
Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
15.00
自引率
1.40%
发文量
231
审稿时长
40 days
期刊介绍: Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.
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