title: A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy.
abstract: Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer.
authors.affiliation: Center for Infection Disease and Signal Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tsung-I
authors.initials: TI
authors.lastname: Hsu
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ying-Jung
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Hung
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yi-Chang
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Sin-Jin
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.affiliation: Center for Infection Disease and Signal Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Sang-Yong
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Masuo
authors.initials: M
authors.lastname: Goto
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Laboratory of Pharmacognosy, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kashiwada
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.|Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Center for Infection Disease and Signal Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Center for Infection Disease and Signal Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jan-Jong
authors.initials: JJ
authors.lastname: Hung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D053978:Pentacyclic Triterpenes; D011379:Prognosis; D014162:Transfection; D014315:Triterpenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000094062:Betulinic Acid
chemical_list: D000970:Antineoplastic Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D000094062:Betulinic Acid
keywords: ER stress; SYK023; metastasis; synaptopodin