title: (-)-β-hydrastine suppresses the proliferation and invasion of human lung adenocarcinoma cells by inhibiting PAK4 kinase activity.
abstract: (-)-β-hydrastine is one of the main active components of the medicinal plant, Hydrastis canadensis, which is used in many dietary supplements intended to enhance the immune system. However, whether (-)-β-hydrastine affects the tumor signaling pathway remains unexplored. In the present study, we found that (-)-β-hydrastine inhibited the kinase activity of p21-activated kinase 4 (PAK4), which is involved in the regulation of cytoskeletal reorganization, cell proliferation, gene transcription, oncogenic transformation and cell invasion. In the present study, (-)-β-hydrastine suppressed lung adenocarcinoma cell proliferation by inhibiting expression of cyclin D1/D3 and CDK2/4/6, leading to cell cycle arrest at the G1 phase, in a PAK4 kinase-dependent manner. Moreover, inhibition of PAK4 kinase activity by (-)-β-hydrastine also promoted the early apoptosis of lung adenocarcinoma cells through the mitochondrial apoptosis pathway. In addition, (-)-β-hydrastine significantly suppressed the migration and invasion of human lung adenocarcinoma cells in conjunction with concomitant blockage of the PAK4/LIMK1/cofilin, PAK4/SCG10 and PAK4/MMP2 pathways. All of these data indicate that (-)-β-hydrastine, as a novel PAK4 inhibitor, suppresses the proliferation and invasion of lung adenocarcinoma cells. Taken together, these results provide novel insight into the development of a PAK4 kinase inhibitor and a potential therapeutic strategy for lung cancer.
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Chinese Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Chinese Ministry of Education, China Medical University, Shenyang North New Area, Shenyang, Liaoning 110122, P.R. China.
authors.forename: Bingyu
authors.initials: B
authors.lastname: Guo
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Chinese Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Chinese Ministry of Education, China Medical University, Shenyang North New Area, Shenyang, Liaoning 110122, P.R. China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery of the Chinese Ministry of Education, Shenyang Pharmaceutical University, Shenhe, Shenyang, Liaoning 110016, P.R. China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Chinese Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Chinese Ministry of Education, China Medical University, Shenyang North New Area, Shenyang, Liaoning 110122, P.R. China.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery of the Chinese Ministry of Education, Shenyang Pharmaceutical University, Shenhe, Shenyang, Liaoning 110016, P.R. China.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery of the Chinese Ministry of Education, Shenyang Pharmaceutical University, Shenhe, Shenyang, Liaoning 110016, P.R. China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Chinese Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Chinese Ministry of Education, China Medical University, Shenyang North New Area, Shenyang, Liaoning 110122, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D044182:Benzylisoquinolines; C013024:hydrastine; C116367:PAK4 protein, human; D054462:p21-Activated Kinases