Molecule Information

General Information of the Molecule (ID: Mol04376)

• Name: Palmitoyl-protein thioesterase 1 (PPT1) ,Homo sapiens
• Synonyms: Palmitoyl-protein hydrolase 1
• Molecule Type: Protein
• Gene Name: PPT1
• Gene ID: 5538
• Sequence:
  MASPGCLWLLAVALLPWTCASRALQHLDPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEK
  KIPGIYVLSLEIGKTLMEDVENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQ
  F LRAVAQRCPSPPMINLISVGGQHQGVFGLPRCPGESSHICDFIRKTLNAGAYSKVVQE
  RL VQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKNLMALKKFVMVKFLNDSIVD
  PVD SEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDHLQLSEEW
  FYAH IIPFLG
• Function: Has thioesterase activity against fatty acid thioesters with14 -18 carbons, including palmitoyl-CoA, S-palmitoyl-N-acetylcysteamine, and palmitoylated proteins . In contrast to PPT2, PPT1 canhydrolyze palmitoylated proteins and palmitoylcysteine. {ECO:0000269|PubMed:12855696,ECO:0000269|PubMed:26731412, ECO:0000269|PubMed:8816748}.
• Uniprot ID: PPT1_HUMAN
• Ensembl ID: ENSG0000013123818
• HGNC ID: HGNC:9325

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Lucanthone

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Glioma [ICD-11: 2A00.1] [1]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Sensitive Drug: Lucanthone
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Luciferase+ GL261 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: GBM43 cells; Brain; Homo sapiens (Human); CVCL_E5GD
• In Vitro Model: GBM9 cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: C57/Bl6 mice modle; Murine glioma model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemistry; Western blot assay; Molecular docking assay
• Mechanism Description: Lucanthone efficiently abates stemness in patient-derived GSC and reduces tumor microtube formation in GSC, an emerging hallmark of treatment resistance in GBM. In glioma tumors derived from cells with acquired resistance to TMZ, lucanthone retains the ability to perturb tumor growth, inhibits autophagy by targeting lysosomes, and reduces Olig2 positivity. We also find that lucanthone may act as an inhibitor of palmitoyl protein thioesterase 1. Our results suggest that lucanthone may function as a potential treatment option for GBM tumors that are not amenable to TMZ treatment. SIGNIFICANCE STATEMENT: We report that the antischistosome agent lucanthone impedes tumor growth in a preclinical model of temozolomide-resistant glioblastoma and reduces the numbers of stem-like glioma cells. In addition, it acts as an autophagy inhibitor, and its mechanism of action may be via inhibition of palmitoyl protein thioesterase 1. As there are no defined therapies approved for recurrent, TMZ-resistant tumor, lucanthone could emerge as a treatment for glioblastoma tumors that may not be amenable to TMZ both in the newly diagnosed and recurrent settings.

References

• Ref 1: Lucanthone, a Potential PPT1 Inhibitor, Perturbs Stemness, Reduces Tumor Microtube Formation, and Slows the Growth of Temozolomide-Resistant Gliomas In Vivo. J Pharmacol Exp Ther. 2024 Mar 15;389(1):51-60.