1 Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California.
2 School of Health Sciences, Wuhan University, Wuhan, China.
Antioxid Redox Signal. 2019 Jun 10;30(17):1983-1998. doi: 10.1089/ars.2017.7486. Epub 2018 Jul 13.
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. We observed that high glucose (HG), 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 , 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 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. 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. . 30, 1983-1998.
流行病学证据表明，糖尿病可能会增加癌症患者罹患乳腺癌（BC）和死亡的风险。糖尿病和癌症之间的病理生理关系尚未完全阐明，迫切需要针对糖尿病相关 BC 的个性化治疗方法。我们观察到，高葡萄糖（HG）会激活核磷酸酶 PP2Cδ，抑制 p53 功能，从而促进 BC 细胞增殖、迁移和侵袭。高血糖症 BC 患者肿瘤组织中的 PP2Cδ 表达高于血糖正常的患者。HG 刺激 PP2Cδ 的机制涉及经典/新型蛋白激酶-C（PKC）的激活和 GSK3β的磷酸化。活性氧（ROS）/NF-κB 通路也介导了 HG 诱导的 PP2Cδ。此外，我们通过基于细胞的生长抑制筛选试验和一组姜黄素模拟物的活性鉴定出 1,5-二杂芳基戊-1,4-二烯-3-酮（化合物 C23）作为一种新型有效的 PP2Cδ 抑制剂，对 MCF-7 细胞具有显著的细胞毒性。除了直接抑制 PP2Cδ 活性外，C23 还能阻断 HG 诱导的 PP2Cδ 表达、热休克蛋白 27（HSP27）诱导以及随后的 ROS/NF-κB 激活。因此，C23 可以显著阻断 HG 触发的 p53 活性抑制，从而抑制癌细胞增殖、迁移和侵袭。此外，高血糖症促进糖尿病裸鼠的 BC 发展，C23 抑制异种移植 BC 肿瘤的生长。我们的研究结果阐明了可能导致糖尿病相关 BC 进展的机制，并为糖尿病患者提供了支持使用可能的替代治疗方法治疗 BC 的首个证据。1983-1998 年。
