title: The TRIB3-SQSTM1 interaction mediates metabolic stress-promoted tumorigenesis and progression via suppressing autophagic and proteasomal degradation.
abstract: Cancer and diabetes are 2 multifactorial chronic diseases with tremendous impact on health worldwide. Metabolic risk factors play a critical role in fueling a wide range of cancers, but with undefined mechanisms. We recently reported that TRIB3, a stress-induced protein, mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin-IGF1 to malignant promotion. We found that several human cancer tissues express higher TRIB3 and phosphorylated IRS1 (insulin receptor substrate 1), which correlates negatively with patient prognosis. Silencing of TRIB3 not only restores insulin-IGF1-suppressed autophagic flux, but also attenuates tumor growth and metastasis. TRIB3 physically interacts with the autophagic receptor SQSTM1, and this interaction hinders the binding of SQSTM1 to LC3 and ubiquitinated proteins, leading to SQSTM1 accumulation and clearance inhibition of ubiquitinated proteins. Interrupting the TRIB3-SQSTM1 interaction with an α-helical peptide derived from SQSTM1 attenuates tumor growth and metastasis through activating autophagic flux. Our findings indicate that TRIB3 links insulin-IGF1 to cancer development and progression through interacting with SQSTM1. Thus, interrupting the TRIB3-SQSTM1 interaction may provide a potential strategy against cancers in patients with diabetes.
authors: a Immunology and Cancer Pharmacology Group; State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Institute of Materia Medica; Chinese Academy of Medical Sciences and Peking Union Medical College ; Beijing , China.
authors: Fang
authors: F
authors: Hua
authors: b Institute of Medicinal Biotechnology; Chinese Academy of Medical Sciences and Peking Union Medical College ; Beijing , China.
authors: Ke
authors: K
authors: Li
authors: a Immunology and Cancer Pharmacology Group; State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Institute of Materia Medica; Chinese Academy of Medical Sciences and Peking Union Medical College ; Beijing , China.
authors: Jiao-Jiao
authors: JJ
authors: Yu
authors: a Immunology and Cancer Pharmacology Group; State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Institute of Materia Medica; Chinese Academy of Medical Sciences and Peking Union Medical College ; Beijing , China.
authors: Zhuo-Wei
authors: ZW
authors: Hu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D063646:Carcinogenesis / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D057149:Ubiquitinated Proteins
keywords: diabetes; metastasis; protein-protein interactions; tumorigenesis; α-helical peptide