title: 5-Fluorouracil inhibits cell migration by induction of Sestrin2 in colon cancer cells.
abstract: 5-Fluorouracil (5-FU) is a chemotherapeutic agent used in the treatment of colorectal cancer. In this study, we investigated whether 5-FU induces Sestrin2 (SESN2), an antioxidant enzyme, and the role of SESN2 in 5-FU action in colon cancer cells. We found that 5-FU upregulated SESN2 protein expression in both HCT116 and HT29 cells. It also increased transcripts of SESN1 and SESN2, but not of SESN3. Furthermore, we investigated whether production of reactive oxygen species (ROS) was involved in 5-FU-induced SESN2 expression. 5-FU did not increase ROS production nor affect Nrf2 phosphorylation and expression levels. Moreover, SESN2 upregulation by 5-FU was not prevented by pretreatment with antioxidants. Next, we investigated p53 levels after 5-FU treatment to elucidate the regulation of SESN2 by 5-FU. An increase in p53 levels was detected following 5-FU treatment; pifithrin-α, an inhibitor of p53 activation, reversed 5-FU-induced SESN2 expression. 5-FU prevented serum-induced in vitro cell migration, but knockdown of SESN2 or treatment with pifithrin-α reversed a 5-FU-mediated decrease in cell migration. Taken together, our results suggest that 5-FU increases SESN2 levels via a p53-dependent pathway, which contributes to inhibition of cancer cell migration in vitro.
authors.affiliation: College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 501-759, South Korea.
authors.forename: Kyuhwa
authors.initials: K
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 501-759, South Korea.
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Ki
authors.affiliation: College of Pharmacy, Mokpo National University, Muan-gun, Jeonnam, 534-729, South Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Park
authors.affiliation: College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 501-759, South Korea. smshin@chosun.ac.kr.
authors.forename: Sang Mi
authors.initials: SM
authors.lastname: Shin
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D019073:HT29 Cells; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation; D000084622:Sestrins
chemical_list: D000964:Antimetabolites, Antineoplastic; D000975:Antioxidants; D052160:Benzothiazoles; D005472:Fluorouracil; D006360:Heat-Shock Proteins; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014050:Toluene; D016159:Tumor Suppressor Protein p53; C495635:NFE2L2 protein, human; C117338:SESN1 protein, human; D000084622:Sestrins; C465398:SESN2 protein, human; C485523:SESN3 protein, human; C495901:TP53 protein, human; C121565:pifithrin
keywords: 5-Fluorouracil; Cell migration; Colorectal cancer; Sestrin2; p53