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Mitomycin C and doxorubicin elicit conflicting signals by causing accumulation of cyclin E prior to p21(WAF1/CIP1) elevation in human hepatocellular carcinoma cells

Cited 4 time in Web of Science Cited 5 time in Scopus
Authors
Choi, Sun-Young; Shen, Yan Nan; Woo, Seon Rang; Yun, Miyoung; Park, Jeong-Eun; Ju, Yeun-Jin; Jeong, Jaemin; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun-Ran; Lee, Jung-Kee; Kim, Sang Hoon; Cho, Myung-Haing; Kong, In-Soo; Lee, Kee-Ho
Issue Date
2012-01
Citation
International Journal of Oncology, Vol.40 No.1, pp.277-286
Keywords
cyclin Ep21(WAF1/CIP1)mitomycin Cdoxorubicinhepatocellular carcinoma
Abstract
Proteins involved in the G, phase of the cell cycle are aberrantly expressed, sometimes in mutated forms, in human cancers including human hepatocellular carcinoma. Upon attack by a DNA-damaging anticancer drug, a cell arrests at the G, phase; this is a safety feature prohibiting entry of DNA-damaged cells into S-phase. p21(WAF1/CIP1) prevents damaged cells from progressing to the next cell cycle. Here, we show that, in response to mitomycin C and doxorubicin, human hepatocellular carcinoma cells generate conflicting signals, mediated by cycl in E and p21(WAF1/CIP1), which respectively accelerates and represses cell cycle transition. Exposure to these anticancer drugs led to rapid accumulation of cyclin E in both p53-proficient HepG2 and p53-deficient Hep3B cells. Such anticancer drug-induced cyclin E accumulation influenced the G(1)-S-phase transition, but not DNA fragmentation-mediated death. In p53-proficient HepG2 cells, accumulation of cyclin E was followed by an increase in the level of p53-dependent p21(WAF1/CIP1), thereby inhibiting further the G(1)-S-phase transition. Sublethal drug concentrations also induced rapid accumulation of cyclin E. but p21(WAF1/CIP1) accumulation was delayed, further facilitating the CO-phase transition. Eventually, most cells arrested in G(2)/M. Thus, mitomycin C- or doxorubicin-induced conflicting signals, mediated by cyclin E and p21(WAF1/CIP1), are in play in human hepatocellular carcinoma cells. Damaged G, cells either immediately enter S-phase, or do not do so at all, depending on the extent of DNA damage.
ISSN
1019-6439
URI
https://hdl.handle.net/10371/172396
DOI
https://doi.org/10.3892/ijo.2011.1184
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Journal Papers (저널논문_수의학과)
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