YSY01A, a Novel Proteasome Inhibitor, Induces Cell Cycle Arrest on G2 Phase in MCF-7 Cells via ERα and PI3K/Akt Pathways

Bingjie Xue; Wei Huang; Xia Yuan; Bo Xu; Yaxin Lou; Quan Zhou; Fuxiang Ran; Zemei Ge; Runtao Li; Jingrong Cui

doi:10.7150/jca.10733

YSY01A, a Novel Proteasome Inhibitor, Induces Cell Cycle Arrest on G2 Phase in MCF-7 Cells via ERα and PI3K/Akt Pathways

J Cancer. 2015 Feb 6;6(4):319-26. doi: 10.7150/jca.10733. eCollection 2015.

Authors

Bingjie Xue¹, Wei Huang¹, Xia Yuan¹, Bo Xu², Yaxin Lou³, Quan Zhou¹, Fuxiang Ran¹, Zemei Ge⁴, Runtao Li⁴, Jingrong Cui¹

Affiliations

¹ 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 100083, Beijing, China;
² 2. Instrumental Analysis Center of State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 100083, Beijing, China;
³ 3. Lab of Proteomics Medical and Healthy Analytical Center, Peking University, Beijing, China;
⁴ 4. Peking University School of Pharmaceutical Sciences Department of Medicinal Chemistry, Beijing, China.

Abstract

Given that the proteasome is essential for multiple cellular processes by degrading diverse regulatory proteins, inhibition of the proteasome has emerged as an attractive target for anti-cancer therapy. YSY01A is a novel small molecule compound targeting the proteasome. The compound was found to suppress viability of MCF-7 cells and cause limited cell membrane damage as determined by sulforhodamine B assay (SRB) and CytoTox 96(®) non-radioactive cytotoxicity assay. High-content screening (HCS) further shows that YSY01A treatment induces cell cycle arrest on G2 phase within 24 hrs. Label-free quantitative proteomics (LFQP), which allows extensive comparison of cellular responses following YSY01A treatment, suggests that various regulatory proteins including cell cycle associated proteins and PI3K/Akt pathway may be affected. Furthermore, YSY01A increases p-CDC-2, p-FOXO3a, p53, p21(Cip1) and p27(Kip1) but decreases p-Akt, p-ERα as confirmed by Western blotting. Therefore, YSY01A represents a potential therapeutic for breast cancer MCF-7 by inducing G2 phase arrest via ERα and PI3K/Akt pathways.

Keywords: ERα; High-content screening; Label-free quantitative proteomics; MCF-7; PI3K/Akt pathways; PS341; YSY01A.