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.
Highlights
High insulin/IGF is a biologic link between diabetes and cancers, but the underlying molecular mechanism remains unclear
Using human tumour tissue microarrays with hepatocellular carcinoma (HCC), colon cancer and lung cancer, we found that higher level of Tribbles homolog 3 (TRB3) was expressed in tumour tissues than in adjacent non-tumour tissues (Fig. 1a–c)
A positive correlation was observed between TRB3 and phosphorylated insulin receptor substrate 1 (pIRS-1) levels in these tumour tissues (Supplementary Table 1)
Summary
High insulin/IGF is a biologic link between diabetes and cancers, but the underlying molecular mechanism remains unclear. 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. TRB3 depletion protects against tumour-promoting actions of insulin/IGF and attenuates tumour initiation, growth and metastasis in mice. Metabolic stresses including Insulin/IGF-1 enhance the expression of TRB3 in a diversity of human tumour tissues and cancer cells. TRB3 depletion protects against the tumour-promoting actions of insulin/IGF in cancer cells and suppresses tumour initiation, and growth and metastasis in mice. Our study reveals a previously unrecognized tumour-promoting mechanism for stress protein TRB3 and opens the possibility of targeting this interaction as a potential strategy against cancers with diabetes
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