Type 2 diabetes is a serious and growing health problem worldwide. Clinical and epidemiologic studies have shown that diabetes carries an increased risk for different forms of cancer, but with undefined mechanisms. High insulin and IGF-1 in circulation have been considered to be the most potential biologic links between the two diseases. However, clinical trials show that targeting insulin/IGF-1 signal does not produce satisfactory efficacy against cancers. Prof. Zhuo-Wei Hu's group in State Key Laboratory of Bioactive Substance and Function of Natural Medicines revealed that TRB3 is a molecular link connecting diabetes to cancer promotion.
Under the supervision of Prof. Zhuo-Wei Hu, Fang Hua, Ke Li, Jiao-Jiao Yu and their colleagues identify there exists a positive correlation between TRB3 and phosphorylated insulin receptor substrate 1 levels in several tumor tissues. Metabolic factors can induce upregulation of TRB3 which interacts with autophagic receptor p62 and hinders p62 binding to LC3 and ubiquitinated substrates, causing p62 accumulation and ubiquitin-proteasome suppression. Hence, accumulation of P62 and other critical tumor-promoting factors induces tumorigenesis and tumor progression. Interrupting the TRB3/P62 interaction by an a-helical peptide derived from P62 produces autophagy-inducing effect and potent anti-tumor efficacies, which confers for targeting this interaction as a potential strategy against certain cancers with diabetes. These findings provide new insights and mechanisms for the connections of diabetes and cancers.
This study entitled "TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations" was published online byNature Communications on Aug 13, 2015.
