Abstract B19: Compound 23 inhibits high glucose-induced breast cancer progression in vivo through regulating activity and expression of PP2Cδ

Abstract

Abstract Epidemiologic evidence suggests that women with diabetes have increased risk of breast cancer. Moreover, diabetes may dramatically increase mortality in patients with cancer, and there exists some important distinction between the breast cancer patients with and without diabetes in the regimen selection and outcomes of cancer therapy. There is an urgent need for more effective and specific clinical treatment for diabetes-associated breast cancer. Our previous studies have suggested that hyperglycemia, via PKC/GSK3β and ROS/NF-κB pathways that are involved in PP2Cδ activation, suppresses the tumor-suppressor p53 function and inhibits DNA damage-induced apoptosis, inducing proliferation in the epithelium and the development of breast cancer. HG inhibition of p53 activity and induction of cancer cell proliferation, migration, and invasion were significantly blocked by CCT007093, a known PP2Cδ inhibitor. The structure similarity between a group of curcumin mimics (compounds 1-33) and CCT007093 spurred us to investigate the inhibitory ability of compounds 1-33 on PP2Cδ. The growth inhibition assay screening identified that compound 23 (C19H26N4O) has a striking cytotoxicity on MCF-7 cells instead of MCF-12A cells versus CCT007093. More interestingly, the impressive cytotoxicity of 23 is fully mirrored by their much stronger inhibitory ability on PP2Cδ in cells (as assessed by phospho-P38 measurement) than CCT007093. Docking simulation for binding modes of these inhibitors to PP2Cδ phosphatase domain suggests that the carbonyl oxygen and the nitrogen on the heteroaromatic ring of compound 23 form two hydrogen bonds with side chains of Arg258 and Asp105, respectively. This leads to a stable binding model of compound 23, which is inconsistent with its stronger inhibition on PP2Cδ. Furthermore, compound 23 dramatically induces heat shock protein 27 (Hsp27), ablating HG-induced ROS production and NF-κB activation, which partially blocked HG induction of PP2Cδ protein expression. Thus, compound 23 significantly blocked HG inhibition of p53 activity and induction of cancer cell proliferation, migration, and invasion. Finally, using streptozotocin (STZ)-induced diabetic nude mice bearing MCF-7 cells, we demonstrate that hyperglycemia promoted the development of breast cancer in vivo and that compound 23 significantly inhibited xenografted breast cancer growth in mice. Taken together, these results suggest that the identified novel PP2Cδ inhibitor compound 23 inhibits HG-induced breast cancer progression in vivo through regulating expression and activity of PP2Cδ. These findings provide the first evidence proposing an alternative approach for the therapy of breast cancer patients with diabetes. Citation Format: Ke Wu, Xiaoting Yu, Xianghua Yi, Zhimin Huang, Ying-Li Wu, Yahya Elshimali, Yanjun Liu, Donghui Zhu, Shilong Zheng, Qiao-Hong Chen, Guangdi Wang, Yong Wu, Jaydutt V. Vadgama. Compound 23 inhibits high glucose-induced breast cancer progression in vivo through regulating activity and expression of PP2Cδ [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B19.