TRIB3-P62 interaction, diabetes and autophagy

Type 2 diabetes (T2D) and cancer are two common diseases with tremendous impact on health worldwide. Epidemiologic evidence suggests that cancer incidence is associated with diabetes as well as certain diabetic risk factors and diabetic medications. Generally, hyperinsulinemia and high level of circulating Insulin-like growth factor 1 (IGF-1) contribute to cancer development through the insulin/IGF’s growth-promoting effect [1, 2]. Medications used to treat T2D can influence some of these factors and may decrease or increase the risk of cancer and cancer-related mortality [3]. Although insulin and IGF-1 have been long assumed as biological links between energy metabolic disorders and cancers, the underlining mechanism remains incompletely understood. Tribbles 3 (TRIB3) is a member of Tribbles homolog family which belongs to the pseudokinase. TRIB3 contains a variant kinase domain, but lacks the adenosine 5’-triphosphate (ATP)-binding and catalytic core motifs. Several studies suggest that TRIB3 expression is increased in response to various stresses, including nutrient deficiency, endoplasmic reticulum stress, oxidative stress and many metabolic stresses, such as hypoxia, hyperglycemia and hyperinsulinemia. Emerging literatures have described important effects for TRIB3 in the regulation of glucose and lipid homeostasis. Recently, several groups including us identify TRIB3 being a crucial player in the regulation of tumorigenesis and tumor progression. We thus suspect TRIB3 acts as a bridge to connect the metabolic risk factors to tumor promotion. Indeed, we demonstrate that metabolic stresses enhance the TRIB3-mediated malignancy-promoting actions [4]. TRIB3 directly interacts with autophagic receptor P62 to interfere with the binding of P62 to LC3 and to ubiquitinated proteins, which results in the defect of P62-mediated selective autophagy and autophagy-dependent clearance of ubiquitinated proteins, and subsequently bothers the ubiquitin-proteasomedependent degradation. A number of cancer-promoting factors including EGFR, COX-2, MMP1/2, MT-MMP, c-Myc, as well as Snail and Twist accumulate in the cells due to the dysfunction of the two major routes for intracellular protein degradation. Interrupting the TRIB3/ P62 interaction by a P62-derived α-helical peptide inhibits tumor initiation, growth and metastasis, and thus increases animal survival through restoring the selective autophagy degradation and accelerating the ubiquitin proteasome system (UPS) clearance of the tumor-promoting factors. Much of the research state that insulin and IGF-1 are the critical biologic link between diabetes and cancer depending on their pro-mitogenic, pro-angiogenesis, pro-migration and pro-glycolysis effects. However, there is controversy regarding to the pro-mitogenic effects as the mechanisms of insulin/IGF-1 for cancer development. For instance, Weinberg points out that the primary role of insulin/IGF-1 is not to turn on the Warburg effect or promote proliferation but suppress cell-suicide mechanisms [1]. In fact, recent clinical trials show that targeting insulin/IGF-1 signal does not produce satisfactory efficacy against cancers [2]. Our studies document that antagonism of insulin/IGF signaling producing an unsatisfactory efficacy against cancer may be attributed to the high expression level of TRIB3 induced Editorial