PXD032120
PXD032120 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Targeting UGCG-dependent lipid raft formation overcomes resistance to lysosomal autophagy inhibition |
| Description | Lysosomal autophagy inhibition (LAI) is a promising approach for cancer therapy when combined with targeted or immunotherapy. LAI with hydroxychloroquine (HCQ) or dimeric chloroquine DC661 can produce single agent antitumor activity but regrowth of tumors is common. To understand potential resistance mechanisms to LAI, we used melanoma as a model. Whole cell proteome analysis of a human melanoma line (A375P) showed that multiple proteins involved in cholesterol and sphingolipid metabolism were induced by LAI, with a predominant increase in the UDP-glucose ceramide glucosyltransferase (UGCG). These protein changes were consistently seen in a panel of non-melanoma human cancer cell lines. Lipidome analysis showed that LAI increased cholesterol, sphingolipid, and glycosylated ceramide levels, all components of lipid rafts. LAI significantly increased lipid raft formation in both the plasma membrane and lysosomes. An extensive chemical screen of sphingolipid and cholesterol metabolism inhibitors identified multiple targets whose inhibition augmented LAI cytotoxicity, but UGCG, a clinically druggable rate-limiting enzyme for glycosphingolipids synthesis, was the most attractive target for further study. Chemical or genetic UGCG inhibition significantly decreased LAI-induced lipid raft formation and augmented lysosomal membrane permeabilization and cell death. Conversely, UGCG overexpression increased lipid raft formation and induced resistance to LAI. DepMap analysis demonstrated that UGCG is a dependency gene in multiple cancer cell lines. In a TCGA dataset, melanoma patients in highest or lowest UGCG expression tertiles had significantly lower overall survival compared to the patients in the middle tertile. The FDA approved UGCG inhibitor eliglustat abrogated LAI-induced lipid raft formation and significantly inhibited tumor growth and improved survival in xenograft, syngeneic tumor model, and a therapy-resistant patient-derived xenograft. In conclusion, UGCG-dependent lipid raft induction is a druggable resistance mechanism to LAI. Clinical trials testing UGCG inhibition in melanoma are feasible and warranted. |
| HostingRepository | MassIVE |
| AnnounceDate | 2022-10-25 |
| AnnouncementXML | Submission_2022-10-25_13:01:25.336.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Aaron Goldman |
| SpeciesList | scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
| ModificationList | Oxidation; Acetyl; Carbamidomethyl |
| Instrument | Q Exactive Plus |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2022-03-08 06:47:01 | ID requested | |
| ⏵ 1 | 2022-10-25 13:01:25 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: Cancer, Melanoma, Lipid Metabolism, Cholesterol Metabolism, Sphingolipid Metabolsim, Autophagy, Cancer Therapy, Proteomics |
Contact List
| Ravi Amaravadi | |
|---|---|
| contact affiliation | University of Pennsylvania |
| contact email | Ravi.Amaravadi@pennmedicine.upenn.edu |
| lab head | |
| Aaron Goldman | |
| contact affiliation | The Wistar Institute |
| contact email | agoldman@wistar.org |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
| Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://massive.ucsd.edu/MSV000089020/ |
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