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Cited by 251Cell death mechanisms and regulationIon Channels and ReceptorsEndoplasmic Reticulum Stress and Disease

PTEN Counteracts FBXL2 to Promote IP3R3- and Ca2+-Mediated Apoptosis Limiting Tumour Growth

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Kuchay, Shafi, Giorgi, Carlotta, Simoneschi, Daniele, Pagan, Julia, Missiroli, Sonia, Saraf, Anita, Florens, Laurence, Washburn, Michael P. +6 more·2017·Nature
DOI 10.1038/nature22965PMC PMC5627969
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Abstract

In response to environmental cues that promote IP3 (inositol 1,4,5-trisphosphate) generation, IP3 receptors (IP3Rs) located on the endoplasmic reticulum allow the 'quasisynaptical' feeding of calcium to the mitochondria to promote oxidative phosphorylation. However, persistent Ca 2+ release results in mitochondrial Ca 2+ overload and consequent apoptosis. Among the three mammalian IP3Rs, IP3R3 appears to be the major player in Ca 2+-dependent apoptosis. Here we show that the F-box protein FBXL2 (the receptor subunit of one of 69 human SCF (SKP1, CUL1, F-box protein) ubiquitin ligase complexes) binds IP3R3 and targets it for ubiquitin-, p97- and proteasome-mediated degradation to limit Ca 2+ influx into mitochondria. FBXL2-knockdown cells and FBXL2-insensitive IP3R3 mutant knock-in clones display increased cytosolic Ca 2+ release from the endoplasmic reticulum and sensitization to Ca 2+-dependent apoptotic stimuli. The phosphatase and tensin homologue (PTEN) gene is frequently mutated or lost in human tumours and syndromes that predispose individuals to cancer. We found that PTEN competes with FBXL2 for IP3R3 binding, and the FBXL2-dependent degradation of IP3R3 is accelerated in Pten-/- mouse embryonic fibroblasts and PTEN-null cancer cells. Reconstitution of PTEN-null cells with either wild-type PTEN or a catalytically dead mutant stabilizes IP3R3 and induces persistent Ca 2+ mobilization and apoptosis. IP3R3 and PTEN protein levels directly correlate in human prostate cancer. Both in cell culture and xenograft models, a non-degradable IP3R3 mutant sensitizes tumour cells with low or no PTEN expression to photodynamic therapy, which is based on the ability of photosensitizer drugs to cause Ca 2+-dependent cytotoxicity after irradiation with visible light. Similarly, disruption of FBXL2 localization with GGTi-2418, a geranylgeranyl transferase inhibitor, sensitizes xenotransplanted tumours to photodynamic therapy. In summary, we identify a novel molecular mechanism that limits mitochondrial Ca 2+ overload to prevent cell death. Notably, we provide proof-of-principle that inhibiting IP3R3 degradation in PTEN-deregulated cancers represents a valid therapeutic strategy.

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Authors
Kuchay, S., Giorgi, C., Simoneschi, D., Pagan, J., Missiroli, S., Saraf, A., Florens, L., Washburn, M. P., Collazo-Lorduy, A., Castillo-Martin, M., Cordon-Cardo, C., Sebti, S. M., Pinton, P., & Pagano, M.
Affiliations
  • Howard Hughes Medical Institute (US)
  • University of Ferrara (IT)
  • NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
  • Stowers Institute for Medical Research (US)
  • Sociedad Española de Oncología Médica (ES)
Corresponding author
  • Pinton, Paolo
  • Pagano, Michele
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2017-06
Volume
546
Issue
7659
Pages
554-558
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature22965
PMC
PMC5627969
OpenAlex
W2626999699
Cited by
251
References
2
Citations by year
2026: 17 · 2025: 21 · 2024: 19 · 2023: 21 · 2022: 28 · 2021: 35 · 2020: 40 · 2019: 27 · 2018: 35 · 2017: 8
FWCI
12.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by)
  • PubMed Central (acceptedVersion, cc-by)
  • Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion, other-oa)
Funders
  • Howard Hughes Medical Institute
  • National Cancer Institute (R01CA076584, R35CA197731, P30CA016087)
  • National Institute of General Medical Sciences (R01GM057587)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
PTEN, IP3R3, IP3 receptor, endoplasmic reticulum calcium release, mitochondrial calcium overload, ubiquitin-mediated proteolysis, SCF ubiquitin ligase, VCP, proteasome, tumour suppressor, photodynamic therapy, tumor growth, cancer therapy resistance, inositol 1,4,5-trisphosphate
MeSH terms
Animals, Binding, Competitive, Calcium, Endoplasmic Reticulum, Fibroblasts, Humans, Male, Mitochondria, Mutation, Photochemotherapy, Prostatic Neoplasms, Protein Binding, Mice, SCID, Mice, Inbred NOD, Apoptosis, Calcium Signaling, Xenograft Model Antitumor Assays, Ubiquitin, F-Box Proteins, Proteasome Endopeptidase Complex, PTEN Phosphohydrolase, Mice, Inositol 1,4,5-Trisphosphate Receptors, HEK293 Cells, Proteolysis

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