Cell Reports Medicine (Sep 2024)
Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma
- 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
Affiliations
- Yaogang Zhong
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Feng Geng
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Logan Mazik
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Xinmin Yin
- Department of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40208, USA
- Aline Paixao Becker
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Shabber Mohammed
- Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy at The Ohio State University, Columbus, OH 43210, USA
- Huali Su
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Enming Xing
- Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy at The Ohio State University, Columbus, OH 43210, USA
- Yongjun Kou
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Cheng-Yao Chiang
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Yunzhou Fan
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Yongchen Guo
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Qiang Wang
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Pui-Kai Li
- Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy at The Ohio State University, Columbus, OH 43210, USA
- Xiaokui Mo
- Center for Biostatistics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- Etienne Lefai
- Human Nutrition Unit, French National Research Institute for Agriculture, Food and Environment, University Clermont Auvergne, 63122 Clermont-Ferrand, France
- Liqing He
- Department of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40208, USA
- Xiaolin Cheng
- Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy at The Ohio State University, Columbus, OH 43210, USA; Translational Data Analytics Institute at The Ohio State University, Columbus, OH 43210, USA
- Xiang Zhang
- Department of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40208, USA
- Arnab Chakravarti
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA
- Deliang Guo
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; Corresponding author
- Journal volume & issue
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Vol. 5,
no. 9
p. 101706
Abstract
Summary: 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.
