Abstract
Cell cycle-arrested cancer cells are resistant to conventional chemotherapy that acts on the mitotic phases of the cell cycle, although the molecular mechanisms involved in halting cell cycle progression remain unclear. Here, we demonstrated that RFPL4A, an uncharacterized ubiquitin ligase, induced G1 retention and thus conferred decreased sensitivity to chemotherapy in the human colorectal cancer cell line, HCT116. Long term time lapse observations in HCT116 cells bearing a "fluorescence ubiquitin-based cell cycle indicator" identified a characteristic population that is viable but remains in the G1 phase for an extended period of time (up to 56 h). Microarray analyses showed that expression of RFPL4A was significantly up-regulated in these G1-arrested cells, not only in HCT116 cells but also in other cancer cell lines, and overexpression of RFPL4A increased the G1 population and decreased sensitivity to chemotherapy. However, knockdown of RFPL4A expression caused the cells to resume mitosis and induced their susceptibility to anti-cancer drugs in vitro and in vivo. These results indicate that RFPL4A is a novel factor that increases the G1 population and decreases sensitivity to chemotherapy and thus may be a promising therapeutic target for refractory tumor conditions.
| Original language | English |
|---|---|
| Pages (from-to) | 6326-6337 |
| Number of pages | 12 |
| Journal | Journal of Biological Chemistry |
| Volume | 290 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Mar 6 2015 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
RFPL4A increases the G1 population and decreases sensitivity to chemotherapy in human colorectal cancer cells. / Naito, Atsushi; Yamamoto, Hirofumi; Kagawa, Yoshinori; Naito, Yoko; Okuzaki, Daisuke; Otani, Keisuke; Iwamoto, Yoriko; Maeda, Sakae; Kikuta, Junichi; Nishikawa, Keizo; Uemura, Mamoru; Nishimura, Junichi; Hata, Taishi; Takemasa, Ichiro; Mizushima, Tsunekazu; Ishii, Hideshi; Doki, Yuichiro; Mori, Masaki; Ishii, Masaru.
In: Journal of Biological Chemistry, Vol. 290, No. 10, 06.03.2015, p. 6326-6337.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - RFPL4A increases the G1 population and decreases sensitivity to chemotherapy in human colorectal cancer cells
AU - Naito, Atsushi
AU - Yamamoto, Hirofumi
AU - Kagawa, Yoshinori
AU - Naito, Yoko
AU - Okuzaki, Daisuke
AU - Otani, Keisuke
AU - Iwamoto, Yoriko
AU - Maeda, Sakae
AU - Kikuta, Junichi
AU - Nishikawa, Keizo
AU - Uemura, Mamoru
AU - Nishimura, Junichi
AU - Hata, Taishi
AU - Takemasa, Ichiro
AU - Mizushima, Tsunekazu
AU - Ishii, Hideshi
AU - Doki, Yuichiro
AU - Mori, Masaki
AU - Ishii, Masaru
PY - 2015/3/6
Y1 - 2015/3/6
N2 - Cell cycle-arrested cancer cells are resistant to conventional chemotherapy that acts on the mitotic phases of the cell cycle, although the molecular mechanisms involved in halting cell cycle progression remain unclear. Here, we demonstrated that RFPL4A, an uncharacterized ubiquitin ligase, induced G1 retention and thus conferred decreased sensitivity to chemotherapy in the human colorectal cancer cell line, HCT116. Long term time lapse observations in HCT116 cells bearing a "fluorescence ubiquitin-based cell cycle indicator" identified a characteristic population that is viable but remains in the G1 phase for an extended period of time (up to 56 h). Microarray analyses showed that expression of RFPL4A was significantly up-regulated in these G1-arrested cells, not only in HCT116 cells but also in other cancer cell lines, and overexpression of RFPL4A increased the G1 population and decreased sensitivity to chemotherapy. However, knockdown of RFPL4A expression caused the cells to resume mitosis and induced their susceptibility to anti-cancer drugs in vitro and in vivo. These results indicate that RFPL4A is a novel factor that increases the G1 population and decreases sensitivity to chemotherapy and thus may be a promising therapeutic target for refractory tumor conditions.
AB - Cell cycle-arrested cancer cells are resistant to conventional chemotherapy that acts on the mitotic phases of the cell cycle, although the molecular mechanisms involved in halting cell cycle progression remain unclear. Here, we demonstrated that RFPL4A, an uncharacterized ubiquitin ligase, induced G1 retention and thus conferred decreased sensitivity to chemotherapy in the human colorectal cancer cell line, HCT116. Long term time lapse observations in HCT116 cells bearing a "fluorescence ubiquitin-based cell cycle indicator" identified a characteristic population that is viable but remains in the G1 phase for an extended period of time (up to 56 h). Microarray analyses showed that expression of RFPL4A was significantly up-regulated in these G1-arrested cells, not only in HCT116 cells but also in other cancer cell lines, and overexpression of RFPL4A increased the G1 population and decreased sensitivity to chemotherapy. However, knockdown of RFPL4A expression caused the cells to resume mitosis and induced their susceptibility to anti-cancer drugs in vitro and in vivo. These results indicate that RFPL4A is a novel factor that increases the G1 population and decreases sensitivity to chemotherapy and thus may be a promising therapeutic target for refractory tumor conditions.
UR - http://www.scopus.com/inward/record.url?scp=84924959504&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84924959504&partnerID=8YFLogxK
U2 - 10.1074/jbc.M114.614859
DO - 10.1074/jbc.M114.614859
M3 - Article
C2 - 25605732
AN - SCOPUS:84924959504
VL - 290
SP - 6326
EP - 6337
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 10
ER -