Abstract
High insulin/IGF is a biologic link between diabetes and cancers, but the underlying molecular mechanism remains unclear. Here we report a previously unrecognized tumour-promoting mechanism for stress protein TRB3, which mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin/IGF to malignant promotion. We find that several human cancers express higher TRB3 and phosphorylated insulin receptor substrate 1, which correlates negatively with patient's prognosis. TRB3 depletion protects against tumour-promoting actions of insulin/IGF and attenuates tumour initiation, growth and metastasis in mice. TRB3 interacts with autophagic receptor p62 and hinders p62 binding to LC3 and ubiquitinated substrates, which causes p62 deposition and suppresses autophagic/proteasomal degradation. Several tumour-promoting factors accumulate in cancer cells to support tumour metabolism, proliferation, invasion and metastasis. Interrupting TRB3/p62 interaction produces potent antitumour efficacies against tumour growth and metastasis. Our study opens possibility of targeting this interaction as a potential novel strategy against cancers with diabetes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Adenine / analogs & derivatives
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Adenine / pharmacology
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Animals
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Autophagy / physiology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Movement
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Gene Expression Regulation, Neoplastic / physiology*
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Humans
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Insulin / metabolism*
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Insulin Receptor Substrate Proteins / genetics
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Insulin Receptor Substrate Proteins / metabolism
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / metabolism*
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Leupeptins / pharmacology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Nude
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Neoplasm Metastasis
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Neoplasms, Experimental
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Proteasome Endopeptidase Complex / physiology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Sequestosome-1 Protein
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Tissue Array Analysis
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Ubiquitin / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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IRS1 protein, human
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Insulin
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Insulin Receptor Substrate Proteins
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Leupeptins
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Repressor Proteins
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SQSTM1 protein, human
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Sequestosome-1 Protein
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TRIB3 protein, human
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Ubiquitin
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3-methyladenine
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Insulin-Like Growth Factor I
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Protein Serine-Threonine Kinases
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Proteasome Endopeptidase Complex
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Adenine
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde