المؤلفون: Zhuo-Wei Hu, Fang Hua, Ting-ting Zhang, Ke Li

المصدر: Autophagy. 14:1278-1279

مصطلحات موضوعية: 0301 basic medicine, Antineoplastic Agents, Biology, Models, Biological, 03 medical and health sciences, 0302 clinical medicine, Autophagy, medicine, Animals, Smad3 Protein, Epigenetics, KAT5, Melanoma, Molecular Biology, Lysine Acetyltransferase 5, Cell Biology, Metformin, Mice, Inbred C57BL, Repressor Proteins, 030104 developmental biology, Tumor progression, 030220 oncology & carcinogenesis, Disease Progression, Commentary, Cancer research, Phosphorylation, Flux (metabolism), medicine.drug

الوصف: Deregulation of metabolism during melanoma progression is tightly associated with the genetic and epigenetic alterations of metabolic regulators. Metformin, a macroautophagy/autophagy inducer, has beneficial effects of preventing and treating multiple cancers with an unclear mechanism. Enhanced pseudokinase TRIB3 was reported to link metabolic stressors to melanoma promotion by inhibiting autophagy and ubiquitin-proteasome degradation systems. Here, we discuss our recent findings regarding how metformin reduces TRIB3 expression to restore autophagic flux and suppress melanoma progression in non-diabetic and diabetic mice. We found that overexpression of TRIB3 reverses the metformin-activated autophagic flux, clearance of accumulated tumor-promoting factors and inhibition of tumor progression. Mechanistically, TRIB3 interacts with KAT5 (lysine acetyltransferase 5) and promotes the physical association of KAT5 and SMAD3, which enhances SMAD3 K333 acetylation in a phosphorylation-dependent manner, sustains SMAD3 transcriptional activity and induces TRIB3 expression. Metformin inhibits SMAD3 phosphorylation and impedes the KAT5-SMAD3 interaction, which attenuates the KAT5-mediated K333 acetylation of SMAD3 to suppress SMAD3 transcriptional activity and TRIB3 expression. Our finding defines a molecular mechanism by which metformin targets TRIB3 expression to induce autophagy and protect against melanoma progression.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b76d5a78872247f23f8b2ebae0a73a2fTest
https://doi.org/10.1080/15548627.2018.1460022Test

المؤلفون: Ke Li, Fang Hua, Zhuo-Wei Hu, Jiao-jiao Yu

المصدر: Autophagy. 11(10)

مصطلحات موضوعية: Carcinogenesis, Autophagy, Cancer, Cell Biology, Biology, medicine.disease_cause, medicine.disease, Ubiquitinated Proteins, Autophagic Puncta, IRS1, Metastasis, Cell biology, Cell Transformation, Neoplastic, Stress, Physiological, Neoplasms, medicine, Gene silencing, Animals, Humans, Receptor, Molecular Biology, Flux (metabolism)

الوصف: 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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5cfd603f34e0e75e0e4dd4b6423210ceTest
https://pubmed.ncbi.nlm.nih.gov/26301314Test

المؤلفون: Fang Hua, Zhuo-Wei Hu, Heng Lin, Ziyan Wang

المصدر: Autophagy. 9(6)

مصطلحات موضوعية: Senescence, Ku80, Carcinoma, Hepatocellular, DNA Repair, DNA repair, DNA damage, Carcinogenesis, Biology, medicine.disease_cause, Models, Biological, medicine, Autophagy, Animals, Humans, Molecular Biology, Ku Autoantigen, Cellular Senescence, Ku70, Liver Neoplasms, Antigens, Nuclear, Cell Biology, digestive system diseases, Autophagic Punctum, Non-homologous end joining, DNA-Binding Proteins, Toll-Like Receptor 4, Cancer research, Reactive Oxygen Species, Cell aging, DNA Damage

الوصف: Hepatocellular carcinoma (HCC) is among the most lethal and prevalent cancers in the human population. The initiation and progression of HCC is closely associated with chronic liver inflammation. Recent research indicates that nonhomologous end joining (NHEJ), one of the DNA repair mechanisms, autophagy and senescence are all involved in the pathogenesis of HCC induced by carcinogens or oxidative stress. DNA repair proteins including XRCC6/KU70 and XRCC5/KU80 are the critical NHEJ factors that play pivotal roles in genome-maintenance issues such as DNA replication and repair, telomere maintenance and chromosomal instability. Our studies indicate that a deficiency of toll-like receptor 4 (TLR4)-mediated immune activities results in a decreased expression of XRCC5 and XRCC6 in response to insult by the carcinogen diethylnitrosamine (DEN). This effect causes a failure in DNA repair, and promotes the transformation of precancerous hepatocytes and HCC development. Ectopic expression of XRCC6 protects against HCC initiation and progression by restoring the cellular senescent response and activation of immune networks, which induces an effective autophagic degradation, removes the accumulated reactive oxygen species (ROS), decreases DNA damage, attenuates proliferation, and promotes programmed cell death in TLR4-deficient livers. Our work indicates that repairing DNA damage by XRCC6 reverses TLR4-deficiency-worsened HCC development via restoring immunity to support senescence and autophagy in liver cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4a7e68558f40d00d2496644929f5edcaTest
https://pubmed.ncbi.nlm.nih.gov/23518600Test

المؤلفون: Zhe Li, Su Mi, Fang Hua, Hong Liu, Zhuo-Wei Hu

المصدر: Autophagy. 9(5)

مصطلحات موضوعية: Class I Phosphatidylinositol 3-Kinases, Pulmonary Fibrosis, Biology, Bleomycin, Glycogen Synthase Kinase 3, Mice, Phosphatidylinositol 3-Kinases, Phosphoserine, GSK-3, immune system diseases, hemic and lymphatic diseases, Pulmonary fibrosis, medicine, Autophagy, Animals, Humans, Cycloheximide, Phosphorylation, Molecular Biology, neoplasms, Lung, PI3K/AKT/mTOR pathway, Glycogen Synthase Kinase 3 beta, Kinase, Protein Stability, Interleukin-17, Ubiquitination, Membrane Proteins, Epithelial Cells, Cell Biology, BECN1, medicine.disease, Basic Research Paper, Cell biology, Enzyme Activation, Proto-Oncogene Proteins c-bcl-2, Proteolysis, Cancer research, Beclin-1, Signal transduction, Apoptosis Regulatory Proteins, Protein Binding

الوصف: We recently found that activation of IL17A signaling promotes the development and progression of acute and chronic pulmonary fibrosis, and that the blockade of IL17A activity attenuates pulmonary fibrosis by promoting the resolution of inflammation and the activation of autophagy. Although the induction of autophagy stimulating the collagen degradation in the fibrotic lung tissue has been identified as a mechanism responsible for the antifibrotic role of targeting IL17A, it remains to be clarified how IL17A signaling suppresses autophagy. Here we report that the phosphorylation of B-cell CLL/lymphoma 2 (BCL2), an apoptosis regulatory protein, was inhibited in the presence of IL17A in lung epithelial cells, and this reduction suppressed the ubiquitination degradation of BCL2, which subsequently attenuated autophagy by promoting the interaction of BCL2 and BECN1. We found that IL17A regulated the phosphorylation of BCL2 through activating the phosphoinositide 3-kinase (PI3K)-glycogen synthase kinase 3 β (GSK3B) signaling cascade. In response to IL17A stimulation, PI3K was activated and resulted in phosphorylation of GSK3B at Ser9, which subsequently attenuated the interaction of GSK3B with BCL2. Interrupting the GSK3B and BCL2 interaction precluded the phosphorylation of BCL2 at Ser70, which could trigger the ubiquitination degradation, and restrained the ubiquitination degradation of BCL2. Consequently, a decrease in the BCL2 degradation induced by IL17A resulted in a suppressed autophagy in lung epithelial cells. These findings indicate that the IL17A-PI3K-GSK3B-BCL2 signaling pathway participates in the attenuation of autophagic activity in lung epithelial cells, which is attributed to be primarily responsible for the development and progression of IL17A-induced pulmonary fibrosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d82493597f3c4508fbddb6f1c30c6450Test
https://pubmed.ncbi.nlm.nih.gov/23514933Test