Abstract
Here, we show that the expression of the Golgi-localized serine-threonine kinase protein kinase D3 (PKD3) is elevated in triple-negative breast cancer (TNBC). Using an antibody array, we identified PKD3 to trigger the activation of S6 kinase 1 (S6K1), a main downstream target of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Accordingly, PKD3 knockdown in TNBC cells led to reduced S6K1 phosphorylation, which was associated with impaired activation of mTORC1 at endolysosomal membranes, the accumulation of the mannose 6-phosphate receptor in and the recruitment of the autophagy marker light chain 3 to enlarged acidic vesicles. We further show that PKD3 depletion strongly inhibited cell spreading and proliferation of TNBC cells, identifying this kinase as a potential novel molecular therapeutic target in TNBC. Together, our data suggest that PKD3 in TNBC cells provides a molecular connection between the Golgi and endolysosomal compartments to enhance proliferative mTORC1-S6K1 signaling.
Keywords:
Autophagy; Breast Cancer; Endosomes; Golgi; Lysosomes; Protein Kinase D (PKD); S6 Kinase; mTOR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Breast Neoplasms / therapy
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Cell Line, Tumor
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Cell Proliferation*
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Endosomes / genetics
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Endosomes / metabolism
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Endosomes / pathology
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Female
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Gene Knockdown Techniques
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Golgi Apparatus / genetics
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Golgi Apparatus / metabolism
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Golgi Apparatus / pathology
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Humans
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Lysosomes / genetics
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Lysosomes / metabolism
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Lysosomes / pathology
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Mechanistic Target of Rapamycin Complex 1
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Protein Kinase C / biosynthesis*
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Protein Kinase C / genetics
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Ribosomal Protein S6 Kinases, 70-kDa / genetics
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
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Signal Transduction*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
Substances
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Multiprotein Complexes
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Neoplasm Proteins
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protein kinase C nu
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Mechanistic Target of Rapamycin Complex 1
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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ribosomal protein S6 kinase, 70kD, polypeptide 1
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Protein Kinase C