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PXD032120 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleTargeting UGCG-dependent lipid raft formation overcomes resistance to lysosomal autophagy inhibition
DescriptionLysosomal 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.
ReviewLevelNon peer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterAaron Goldman
SpeciesList scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationListOxidation; Acetyl; Carbamidomethyl
InstrumentQ Exactive Plus
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-03-08 06:47:01ID requested
12022-10-25 13:01:25announced
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 affiliationUniversity of Pennsylvania
contact emailRavi.Amaravadi@pennmedicine.upenn.edu
lab head
Aaron Goldman
contact affiliationThe Wistar Institute
contact emailagoldman@wistar.org
dataset submitter
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Dataset FTP location
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