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Deacetylation of LAMP1 drives lipophagy-dependent generation of free fatty acids by Abrus agglutinin to promote senescence in prostate cancer
Piyush Kumar Gupta,
Published in Wiley-Liss Inc.
2020
PMID: 31544977
Volume: 235
   
Issue: 3
Pages: 2776 - 2791
Abstract
Therapy-induced senescence in cancer cells is an irreversible antiproliferative state, which inhibits tumor growth and is therefore a potent anti-neoplastic mechanism. In this study, low doses of Abrus agglutinin (AGG)-induced senescence through autophagy in prostate carcinoma cells (PC3) and inhibited proliferation. The inhibition of autophagy with 3-methyl adenine reversed AGG-induced senescence, thus confirming that AGG-triggered senescence required autophagy. AGG treatment also led to lipophagy-mediated accumulation of free fatty acids (FFAs), with a concomitant decrease in the number of lipid droplets. Lalistat, a lysosomal acid lipase inhibitor, abrogated AGG-induced lipophagy and senescence in PC3 cells, indicating that lipophagy is essential for AGG-induced senescence. The accumulation of FFAs increased reactive oxygen species generation, a known facilitator of senescence, which was also reduced in the presence of lalistat. Furthermore, AGG upregulated silent mating type information regulator 2 homolog 1 (SIRT1), while the presence of sirtinol reduced autophagy flux and the senescent phenotype in the AGG-treated cells. Mechanistically, AGG-induced cytoplasmic SIRT1 deacetylated a Lys residue on the cytoplasmic domain of lysosome-associated membrane protein 1 (LAMP1), an autolysosomal protein, resulting in lipophagy and senescence. Taken together, our findings demonstrate a novel SIRT1/LAMP1/lipophagy axis mediating AGG-induced senescence in prostate cancer cells. © 2019 Wiley Periodicals, Inc.
About the journal
JournalData powered by TypesetJournal of Cellular Physiology
PublisherData powered by TypesetWiley-Liss Inc.
ISSN00219541
Open AccessNo
Concepts (34)
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    ADIPOPHILIN
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    AGGLUTININ
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    Cyclin b1
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    Cyclin d1
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    CYCLINE
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    FAT DROPLET
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    Fatty acid
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    LALISTAT
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    Lysine
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    Lysosome associated membrane protein 1
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    PHOSPHOLIPASE INHIBITOR
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    Protein p21
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    Reactive oxygen metabolite
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    Retinoblastoma protein
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    SIRTINOL
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    SIRTUIN 1
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    Unclassified drug
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    ABRUS
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    Article
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    Autophagy
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    Controlled study
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    Cytoplasm
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    Deacetylation
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    Human
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    Human cell
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    LIPOPHAGOCYTOSIS
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    Nonhuman
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    PC-3 [HUMAN PROSTATE CARCINOMA] CELL LINE
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    Phenotype
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    Priority journal
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    Prostate cancer
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    Protein domain
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    Senescence
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    Upregulation