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RFPL4A increases the G1 population and decreases sensitivity to chemotherapy in human colorectal cancer cells
Atsushi Naito1, Hirofumi Yamamoto2, Yoshinori Kagawa3
1From the Departments of Immunology and Cell Biology, Gastroenterological Surgery, and.
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.
Insights
RFPL4A, a novel ubiquitin ligase, causes cancer cells to arrest in the G1 phase, reducing chemotherapy effectiveness. Targeting RFPL4A may overcome chemotherapy resistance in refractory tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Cancer cells arrested in the G1 phase exhibit resistance to conventional chemotherapy.
- The molecular mechanisms driving G1 cell cycle arrest and chemotherapy resistance are not fully understood.
Purpose of the Study:
- To investigate the role of the uncharacterized ubiquitin ligase RFPL4A in G1 cell cycle arrest and chemotherapy resistance.
- To identify RFPL4A as a potential therapeutic target for overcoming drug resistance in cancer.
Main Methods:
- Utilized long-term time-lapse microscopy with a fluorescence ubiquitin-based cell cycle indicator in HCT116 cells.
- Performed microarray analyses to identify differentially expressed genes in G1-arrested cells.
- Investigated the effects of RFPL4A overexpression and knockdown on cell cycle progression and chemotherapy sensitivity in vitro and in vivo.
Main Results:
- Identified a subpopulation of viable cancer cells exhibiting prolonged G1 arrest (up to 56 hours).
- RFPL4A expression was significantly upregulated in G1-arrested cells across multiple cancer lines.
- Overexpression of RFPL4A promoted G1 arrest and decreased chemotherapy sensitivity, while RFPL4A knockdown restored mitosis and increased drug susceptibility.
Conclusions:
- RFPL4A is a novel ubiquitin ligase that induces G1 cell cycle arrest, contributing to chemotherapy resistance.
- RFPL4A represents a promising therapeutic target for enhancing the efficacy of chemotherapy in refractory cancers.
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