2. Academic Validation
  3. CIL-102-Induced Cell Cycle Arrest and Apoptosis in Colorectal Cancer Cells via Upregulation of p21 and GADD45

CIL-102-Induced Cell Cycle Arrest and Apoptosis in Colorectal Cancer Cells via Upregulation of p21 and GADD45

  • PLoS One. 2017 Jan 9;12(1):e0168989. doi: 10.1371/journal.pone.0168989.
Wen-Shih Huang 1 2,  Yi-Hung Kuo 1 3,  Hsing-Chun Kuo 4 5 6,  Meng-Chiao Hsieh 1 3,  Cheng-Yi Huang 1,  Ko-Chao Lee 7,  Kam-Fai Lee 8,  Chien-Heng Shen 3 9,  Shui-Yi Tung 2 9,  Chih-Chuan Teng 4 6
Affiliations

Affiliations

  • 1 Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
  • 2 Chang Gung University College of Medicine, Taoyuan, Taiwan.
  • 3 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Chiayi, Taiwan.
  • 4 Department of Nursing, Chang Gung University of Science and Technology, Chiayi, Taiwan.
  • 5 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.
  • 6 Chronic Diseases and Health Promotion Research Center, CGUST, Chiayi, Taiwan.
  • 7 Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
  • 8 Department of Pathology, Chang Gung Memorial Hospital at Chiayi, Taiwan.
  • 9 Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
PMID: 28068431 DOI: 10.1371/journal.pone.0168989
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.

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