PXD036429

PXD036429 is an original dataset announced via ProteomeXchange.

Title	Parallel PP2A activation and importin inhibition by sphingosine and related anti-neoplastic compounds
Description	Sphingolipids enforce homeostatic cell growth in eukaryotes1,2. Phytosphingosine triggers an adaptive growth arrest in heat-stressed yeast while ceramide and its precursor/product sphingosine function as tumor suppressors in mammalian cells. Consistent with this, the constrained cyclic analogs of sphingosine FTY720 and SH-BC-893 limit tumor growth in multiple pre-clinical cancer models3,4. However, the protein targets that mediate the anti-neoplastic effects of sphingosine-like molecules remain poorly defined. Here we show that natural and synthetic sphingosine-like compounds engage the protein phosphatase 2A (PP2A) scaffolding subunit PPP2R1A and the structurally related karyopherins importin-β1 (KPNB1), transportin-1 (TNPO1), importin-5 (IPO5), and importin-7 (IPO7). While sphingosine-like molecules were known to activate PP2A3–6, binding to importins was unexpected. PP2A activation limits nutrient access through effects on endolysosomal trafficking3,7–9, but also triggers the proteasomal degradation of anabolic transcription factors like MYC and the androgen receptor (AR)10,11. Importins are required for oncogenic transcription factors to enter the nucleus and engage their target genes. By activating PP2A and inhibiting importins in parallel, sphingosine-like compounds robustly inhibited prostate cancer drivers YAP, JUN, MYC and the AR as well as other proteins involved in proliferation, metabolism, and protein translation. Sphingosine itself also induced conformational changes in PPP2R1A and KPNB1 and blocked IPO7- and KPNB1-dependent nuclear import. Interestingly, ceramide did not engage these protein targets suggesting that ceramide and sphingosine promote homeostatic cell growth through different mechanisms. These results provide biological insights into the anti-neoplastic actions of sphingosine and related molecules and highlight a possible path towards cancer therapeutics that engage PP2A and importins in parallel, simultaneously targeting multiple difficult-to-drug oncoproteins.
HostingRepository	PRIDE
AnnounceDate	2025-05-14
AnnouncementXML	Submission_2025-05-14_04:55:21.252.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Bonneil
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-31 11:18:31	ID requested
⏵ 1	2025-05-14 04:55:21	announced

Dataset with its publication pending

submitter keyword: PP2A activation, importin inhibition, sphingosine, chemoproteomics

Pierre Thiabult
contact affiliation	IRIC-Université de Montréal
contact email	pierre.thibault@umontreal.ca
lab head
Eric Bonneil
contact affiliation	Proteomic Platform
contact email	eric.bonneil@umontreal.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD036429
     1. Label: PRIDE project
     2. Name: Parallel PP2A activation and importin inhibition by sphingosine and related anti-neoplastic compounds