title: Securin enhances the anti-cancer effects of 6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole (BPR0L075) in human colorectal cancer cells.
abstract: BPR0L075 [6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole] is a novel anti-microtubule drug with anti-tumor and anti-angiogenic activities in vitro and in vivo. Securin is required for genome stability, and is expressed abundantly in most cancer cells, promoting cell proliferation and tumorigenesis. In this study, we found that BPR0L075 efficiently induced cell death of HCT116 human colorectal cancer cells that have higher expression levels of securin. The cytotoxicity of BPR0L075 was attenuated in isogenic securin-null HCT116 cells. BPR0L075 induced DNA damage response, G(2)/M arrest, and activation of the spindle assembly checkpoint in HCT116 cells. Interestingly, BPR0L075 induced phosphorylation of securin. BPR0L075 withdrawal resulted in degradation of securin, mitotic exit, and mitotic catastrophe, which were attenuated in securin-null cells. Inhibition of cdc2 decreased securin phosphorylation, G(2)/M arrest and cell death induced by BPR0L075. Moreover, BPR0L075 caused cell death through a caspase-independent mechanism and activation of JNK and p38 MAPK pathways. These findings provided evidence for the first time that BPR0L075 treatment is beneficial for the treatment of human colorectal tumors with higher levels of securin. Thus, we suggest that the expression levels of securin may be a predictive factor for application in anti-cancer therapy with BPR0L075 in human cancer cells.
authors.affiliation: Department of Life Science, Tzu Chi University, Hualien, Taiwan ROC.
authors.forename: Ho-Hsing
authors.initials: HH
authors.lastname: Tseng
authors.forename: Qiu-Yu
authors.initials: QY
authors.lastname: Chuah
authors.forename: Pei-Ming
authors.initials: PM
authors.lastname: Yang
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Jung-Chi
authors.initials: JC
authors.lastname: Chao
authors.forename: Ming-Der
authors.initials: MD
authors.lastname: Lin
authors.forename: Shu-Jun
authors.initials: SJ
authors.lastname: Chiu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D064249:Securin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C488735:6-methoxy-3-(3',4',5'-trimethoxybenzoyl)-1H-indole; D000970:Antineoplastic Agents; D007211:Indoles; D009363:Neoplasm Proteins; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; D016203:CDC2 Protein Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases