Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma
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.
Authors
- Yongjun Kou (ORCID: https://orcid.org/0000-0003-1096-3161)
- Xinmin Yin (ORCID: https://orcid.org/0000-0001-5716-3458)
- Xiaokui Molly Mo (ORCID: https://orcid.org/0000-0002-9797-2687)
- Arnab Chakravarti (ORCID: https://orcid.org/0000-0002-5392-8721)
- Yunzhou Fan (ORCID: https://orcid.org/0009-0001-9860-0690)
- Shabber Mohammed (ORCID: https://orcid.org/0000-0002-4852-0596)
- Xiaolin Cheng (ORCID: https://orcid.org/0000-0002-7396-3225)
- Aline Paixão Becker (ORCID: https://orcid.org/0000-0002-8695-810X)
- Pui‐Kai Li (ORCID: https://orcid.org/0000-0002-4831-7213)
- Cheng-Yao Chiang
- Étienne Lefai (ORCID: https://orcid.org/0000-0002-3042-7801)
- Yaogang Zhong (ORCID: https://orcid.org/0000-0003-0254-2797)
- Deliang Guo (ORCID: https://orcid.org/0000-0002-8359-390X)
- Xiang Zhang (ORCID: https://orcid.org/0000-0003-1102-6313)
- Qiang Wang (ORCID: https://orcid.org/0000-0002-4918-1338)
- Yongchen Guo
- Feng Geng (ORCID: https://orcid.org/0000-0002-2985-0629)
- Liqing He (ORCID: https://orcid.org/0000-0002-6059-4459)
- Huali Su
- Logan Mazik
- Enming Xing
Institutions
- University of Louisville (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- Unité de Nutrition Humaine (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Centre de Recherche en Nutrition Humaine d'Auvergne (FR)
- The Ohio State University (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101706
- Citations
- 31
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 8.84
Funders
- Pelotonia
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke