Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A

Sphingosine and constrained analogs like FTY720 and SH-BC-893 restrain tumor growth through incompletely defined mechanisms that include protein phosphatase 2A (PP2A) activation. Here we show that these compounds directly bind not only the PP2A scaffolding subunit PPP2R1A, but also the structurally related karyopherins importin-β1 (KPNB1), transportin-1 (TNPO1), importin-5 (IPO5), and importin-7 (IPO7). Binding to sphingosine-like molecules triggers reversible unfolding of these target proteins, resulting in activation of PP2A and inhibition of importins. Although sphingosine engages these proteins, ceramide does not, suggesting that these two endogenous tumor-suppressive sphingolipids work through distinct mechanisms. Simultaneous PP2A activation and importin inhibition reduces nuclear levels of proteins that drive cancer progression and therapeutic resistance such as JUN, YAP, MYC, androgen receptor, hnRNPA1, and NF-κB under conditions where compounds that target PP2A or KPNB1 individually are inactive. These findings provide new insights into sphingolipid biology and highlight a possible path toward cancer therapeutics that could overcome drug resistance.

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Publication Details

Journal
The EMBO Journal
Published
2025-06-30
DOI
https://doi.org/10.1038/s44318-025-00490-5
Citations
1
Primary Topic
Sphingolipid Metabolism and Signaling
Type
article
Field-Weighted Citation Impact
0.81

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Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A

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The EMBO Journal
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article

Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A

Vito Vece, David L. Mobley, Sunhee Jung, Cholsoon Jang, Elizabeth Selwan, Pierre Thibault, Vaishali Jayashankar, Mary Pitman, Alison N. McCracken, Jean-Baptiste Garsi, Kazumi Eckenstein, Ruijuan Xu, Aimee L. Edinger, Éric Bonneil, Peter Kubiniok, Lorenzo Sernissi, Stephen Hanessian, Sarah Y. Valles, Cungui Mao, Brendan T. Finicle, Peter Kaiser, Dawei Lin, N Hoffman, Arielle S Perrochon, Rebeca G Gentry
article en
1 citations

Abstract

Sphingosine and constrained analogs like FTY720 and SH-BC-893 restrain tumor growth through incompletely defined mechanisms that include protein phosphatase 2A (PP2A) activation. Here we show that these compounds directly bind not only the PP2A scaffolding subunit PPP2R1A, but also the structurally related karyopherins importin-β1 (KPNB1), transportin-1 (TNPO1), importin-5 (IPO5), and importin-7 (IPO7). Binding to sphingosine-like molecules triggers reversible unfolding of these target proteins, resulting in activation of PP2A and inhibition of importins. Although sphingosine engages these proteins, ceramide does not, suggesting that these two endogenous tumor-suppressive sphingolipids work through distinct mechanisms. Simultaneous PP2A activation and importin inhibition reduces nuclear levels of proteins that drive cancer progression and therapeutic resistance such as JUN, YAP, MYC, androgen receptor, hnRNPA1, and NF-κB under conditions where compounds that target PP2A or KPNB1 individually are inactive. These findings provide new insights into sphingolipid biology and highlight a possible path toward cancer therapeutics that could overcome drug resistance.

The EMBO JournalVol. 44(16)
State University of New York (US), University of California, Irvine (US), Stony Brook School (US), Institute for Research in Immunology and Cancer (CA), Irvine University (US), Stony Brook University (US), Université de Montréal (CA)
American Diabetes Association, American Cancer Society, Genome Canada, National Research Foundation of Korea, Ono Pharma Foundation, Natural Sciences and Engineering Research Council of Canada, Fonds de Recherche du Québec - Santé, National Cancer Institute, National Institute of General Medical Sciences, DOD Peer Reviewed Cancer Research Program
Good health and well-being
Openalex Percentile: Top 26%
Sphingolipid Metabolism and Signaling
0.81
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