Abstract
The molecular mechanisms underlying the anti-breast cancer effects of polyphyllin I, a natural compound extracted from Paris polyphylla rhizomes, are not fully understood. In the present study, we found that polyphyllin I induces mitochondrial translocation of DRP1 by dephosphorylating DRP1 at Ser637, leading to mitochondrial fission, cytochrome c release from mitochondria into the cytosol and, ultimately apoptosis. Polyphyllin I also increased the stabilization of full-length PINK1 at the mitochondrial surface, leading to the recruitment of PARK2, P62, ubiquitin, and LC3B-II to mitochondria and culminating in mitophagy. PINK1 knockdown markedly suppressed polyphyllin I-induced mitophagy and enhanced polyphyllin I-induced, DRP1-dependent mitochondrial fission and apoptosis. Furthermore, suppression of DRP1 by mdivi-1 or shRNA inhibited PINK1 knockdown/polyphyllin I-induced mitochondrial fragmentation and apoptosis, suggesting that PINK1 depletion leads to excessive fission and, subsequently, mitochondrial fragmentation. An in vivo study confirmed that polyphyllin I greatly inhibited tumor growth and induced apoptosis in MDA-MB-231 xenografts, and these effects were enhanced by PINK1 knockdown. These data describe the mechanism by which PINK1 contributes to polyphyllin I-induced mitophagy and apoptosis and suggest that polyphyllin I may be an effective drug for breast cancer treatment.
Keywords:
DRP1; PINK1; mitochondrial fission; mitophagy; polyphyllin I.
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Autophagy / drug effects*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / enzymology
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Diosgenin / analogs & derivatives*
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Diosgenin / pharmacology
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Dose-Response Relationship, Drug
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Dynamins
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Female
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / metabolism
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Humans
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MCF-7 Cells
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Mice, Nude
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Mitochondria / drug effects*
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Mitochondria / enzymology
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Mitochondria / genetics
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Mitochondria / pathology
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Mitochondrial Dynamics / drug effects
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Mitophagy / drug effects*
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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RNA Interference
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Signal Transduction / drug effects
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Time Factors
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Transfection
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Tumor Burden / drug effects
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Up-Regulation
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Phytogenic
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Apoptosis Regulatory Proteins
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Microtubule-Associated Proteins
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Mitochondrial Proteins
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polyphyllin I
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Ubiquitin-Protein Ligases
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parkin protein
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Protein Kinases
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PTEN-induced putative kinase
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GTP Phosphohydrolases
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DNM1L protein, human
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Dynamins
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Diosgenin