1. Targeting of PP2Cδ By a Small Molecule C23 Inhibits High Glucose-Induced Breast Cancer Progression In Vivo .
- Author
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Wu K, Yu X, Huang Z, Zhu D, Yi X, Wu YL, Hao Q, Kemp KT 2nd, Elshimali Y, Iyer R, Nguyen KT, Zheng S, Chen G, Chen QH, Wang G, Vadgama JV, and Wu Y
- Subjects
- Acetylation, Animals, Antineoplastic Agents chemistry, Breast Neoplasms drug therapy, Cell Line, Tumor, Curcumin analogs & derivatives, Curcumin chemistry, Disease Models, Animal, Disease Progression, Enzyme Inhibitors chemistry, Female, Glycogen Synthase Kinase 3 beta metabolism, Humans, Hyperglycemia, Mice, Models, Molecular, NF-kappa B metabolism, Phosphorylation, Protein Phosphatase 2C chemistry, Reactive Oxygen Species metabolism, Tumor Suppressor Protein p53 metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Curcumin pharmacology, Enzyme Inhibitors pharmacology, Glucose metabolism, Protein Phosphatase 2C antagonists & inhibitors
- Abstract
Aims: Epidemiologic evidence indicates that diabetes may increase risk of breast cancer (BC) and mortality in patients with cancer. The pathophysiological relationships between diabetes and cancer are not fully understood, and personalized treatments for diabetes-associated BC are urgently needed. Results: We observed that high glucose (HG), via activation of nuclear phosphatase PP2Cδ, suppresses p53 function, and consequently promotes BC cell proliferation, migration, and invasion. PP2Cδ expression is higher in tumor tissues from BC patients with hyperglycemia than those with normoglycemia. The mechanisms underlying HG stimulation of PP2Cδ involve classical/novel protein kinase-C (PKC) activation and GSK3β phosphorylation. Reactive oxygen species (ROS)/NF-κB pathway also mediates HG induction of PP2Cδ. Furthermore, we identified a 1,5-diheteroarylpenta-1,4-dien-3-one (Compound 23 , or C23) as a novel potent PP2Cδ inhibitor with a striking cytotoxicity on MCF-7 cells through cell-based screening assay for growth inhibition and activity of a group of curcumin mimics. Beside directly inhibiting PP2Cδ activity, C23 blocks HG induction of PP2Cδ expression via heat shock protein 27 (HSP27) induction and subsequent ablation of ROS/NF-κB activation. C23 can thus significantly block HG-triggered inhibition of p53 activity, leading to the inhibition of cancer cell proliferation, migration, and invasion. In addition, hyperglycemia promotes BC development in diabetic nude mice, and C23 inhibits the xenografted BC tumor growth. Conclusions and Innovation: Our findings elucidate mechanisms that may have contributed to diabetes-associated BC progression, and provide the first evidence to support the possible alternative therapeutic approach to BC patients with diabetes. Antioxid. Redox Signal . 30, 1983-1998.
- Published
- 2019
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