title: CIL-102-Induced Cell Cycle Arrest and Apoptosis in Colorectal Cancer Cells via Upregulation of p21 and GADD45.
abstract: CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone) is a well-known, major active agent of the alkaloid derivative of Camptotheca acuminata with valuable biological properties, including anti-tumorigenic activity. In this study, we investigated the molecular mechanisms by which CIL-102 mediated the induction of cell death, and we performed cell cycle G2/M arrest to clarify molecular changes in colorectal cancer cells (CRC). Treatment of DLD-1 cells with CIL-102 resulted in triggering the extrinsic apoptosis pathway through the activation of Fas-L, caspase-8 and the induction of Bid cleavage and cytochrome c release in a time-dependent manner. In addition, CIL-102 mediated apoptosis and G2/M arrest by phosphorylation of the Jun N-terminus kinase (JNK1/2) signaling pathway. This resulted in the expression of NFκB p50, p300 and CREB-binding protein (CBP) levels, and in the induction of p21 and GADD45 as well as the decreased association of cdc2/cyclin B. Furthermore, treatment with the JNK1/2 (SP600125), NFκB (PDTI) or the p300/CBP (C646) inhibitors abolished CIL-102-induced cell cycle G2/M arrest and reversed the association of cdc2 with cyclin B. Therefore, we demonstrated that there was an increase in the cellular levels of p21 and GADD45 by CIL-102 reduction in cell viability and cell cycle arrest via the activation of the JNK1/2, NFκB p50, p300 and CBP signaling modules. Collectively, our results demonstrated that CIL-102 induced cell cycle arrest and apoptosis of colon cancer cells by upregulating p21 and GADD45 expression and by activating JNK1/2, NFκB p50 and p300 to provide a new mechanism for CIL-102 treatment.
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Wen-Shih
authors.initials: WS
authors.lastname: Huang
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Chiayi, Taiwan.
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Kuo
authors.affiliation: Department of Nursing, Chang Gung University of Science and Technology, Chiayi, Taiwan.|Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.|Chronic Diseases and Health Promotion Research Center, CGUST, Chiayi, Taiwan.
authors.forename: Hsing-Chun
authors.initials: HC
authors.lastname: Kuo
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.|Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Chiayi, Taiwan.
authors.forename: Meng-Chiao
authors.initials: MC
authors.lastname: Hsieh
authors.affiliation: Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Ko-Chao
authors.initials: KC
authors.lastname: Lee
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital at Chiayi, Taiwan.
authors.forename: Kam-Fai
authors.initials: KF
authors.lastname: Lee
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Chiayi, Taiwan.|Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Chien-Heng
authors.initials: CH
authors.lastname: Shen
authors.affiliation: Chang Gung University College of Medicine, Taoyuan, Taiwan.|Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Shui-Yi
authors.initials: SY
authors.lastname: Tung
authors.affiliation: Department of Nursing, Chang Gung University of Science and Technology, Chiayi, Taiwan.|Chronic Diseases and Health Promotion Research Center, CGUST, Chiayi, Taiwan.
authors.forename: Chih-Chuan
authors.initials: CC
authors.lastname: Teng
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011804:Quinolines; D050880:p300-CBP Transcription Factors; D000097642:GADD45 Proteins; C510259:1-(4-(furo(2,3-b)quinolin-4-ylamino)phenyl)ethanone