Ke Wu1,2, Xiaoting Yu3, Zhimin Huang4, Donghui Zhu5, Xianghua Yi3, Ying-Li Wu4, Qiongyu Hao1, Kevin T Kemp1, Yahya Elshimali1, Roshni Iyer6, Kytai Truong Nguyen6, Shilong Zheng7,8, Guanglin Chen9, Qiao-Hong Chen9, Guangdi Wang7,8, Jaydutt V Vadgama1,10, Yong Wu1,10. 1. 1 Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California. 2. 2 School of Health Sciences, Wuhan University, Wuhan, China. 3. 3 Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China. 4. 4 Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 5. 5 Department of Biomedical Engineering, University of North Texas, Denton, Texas. 6. 6 Department of Biomedical Engineering, University of Texas at Arlington, Arlington, Texas. 7. 7 RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, Louisiana. 8. 8 Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana. 9. 9 Department of Chemistry, California State University, Fresno, Fresno, California. 10. 10 David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California.
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.
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.
Entities:
Keywords:
GSK3β; NF-κB; PP2Cδ; breast cancer; diabetes; high glucose; p53
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