title: Mechanistic study of the anti-cancer effect of Gynostemma pentaphyllum saponins in the Apc(Min/+) mouse model.
abstract: Gynostemma pentaphyllum saponins (GpS) have been shown to have anti-cancer activity. However, the underlying mechanisms remain unclear. In this study, we used the Apc(Min) (/+) colorectal cancer (CRC) mouse model to investigate the anti-cancer effect of GpS and we demonstrated that GpS treatment could significantly reduce the number and size of intestinal polyps in Apc(Min) (/+) mice. In order to identify the potential targets and mechanisms involved, a comparative proteomics analysis was performed and 40 differentially expressed proteins after GpS treatment were identified. Bioinformatics analyses suggested a majority of these proteins were involved in processes related to cellular redox homeostasis, and predicted Raf-1 as a potential target of GpS. The upregulation of two proteins known to be involved in redox homeostasis, peroxiredoxin-1 (Prdx1) and peroxiredoxin-2 (Prdx2), and the downregulation of Raf-1 were validated using Western blot analysis. After further investigation of the associated signaling networks, we postulated that the anti-cancer effect of GpS was mediated through the upregulation of Prdx1 and Prdx2, suppression of Ras, RAF/MEK/ERK/STAT, PI3K/AKT/mTOR signaling and modulation of JNK/p38 MAPK signaling. We also examined the potential combinatorial effect of GpS with the chemotherapeutic 5-fluorouracil (5-FU) and found that GpS could enhance the anti-cancer efficacy of 5-FU, further suppressing the number of polyps in Apc(Min/+) mice. Our findings highlight the potential of GpS as an anti-cancer agent, the potential mechanisms of its anti-cancer activities, and its effect as an adjuvant of 5-FU in the chemotherapy of CRC.
authors.affiliation: Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, P. R. China.
authors.forename: William Chi-Shing
authors.initials: WC
authors.lastname: Tai
authors.affiliation: Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, P. R. China.
authors.forename: Wing-Yan
authors.initials: WY
authors.lastname: Wong
authors.affiliation: Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, P. R. China.
authors.forename: Magnolia Muk-Lan
authors.initials: MM
authors.lastname: Lee
authors.affiliation: Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, P. R. China.
authors.forename: Brandon Dow
authors.initials: BD
authors.lastname: Chan
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, P. R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P. R. China.
authors.forename: Wen-Luan Wendy
authors.initials: WL
authors.lastname: Hsiao
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D029774:Gynostemma / Q000737:chemistry; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020543:Proteome / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D000972:Antineoplastic Agents, Phytogenic; D020543:Proteome; D012503:Saponins; C000613192:adenomatous polyposis coli protein, mouse; D005472:Fluorouracil
keywords: Animal proteomics; ApcMin/+ mice; Colorectal cancer; Gynostemma pentaphyllum; Saponins