期刊
CANCERS
卷 12, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/cancers12051240
关键词
topoisomerase 1; colon cancer; phosphorylation; cell heterogeneity; camptothecin
类别
资金
- Carlsberg foundation
- Independent Research Fund Denmark [8021-00052B]
- Novo Nordisk Foundation [0052561]
- Familien Erichsens mindefond
- Aase and Ejnar Danielsen's Foundation
- Aage and Johanne Louis-Hansens Foundation
- Marie and M.B. Richters Foundation
- Minister Erna Hamil- tons Legat for Videnskab og Kunst
- Civilingenior Frode V. Nyegaard og hustrus Fond
- Karen Elise Jensens Foun- dation
- Arvid Nilssons Foundation
- Ludvid og Franciska Andersens legat
- KUs Foundation for Cancer Research
- Danish Cancer Society
- Race Against Breast Cancer foundation
- John and Birthe Meyer Foundation
- Danish National Research Foundation (Centre of Excellence: CARD) [DNRF125]
The heterogeneity of tumor cells and the potential existence of rare cells with reduced chemotherapeutic response is expected to play a pivotal role in the development of drug resistant cancers. Herein, we utilized the colon cancer cell lines, Caco2 and DLD1, to investigate heterogeneity of topoisomerase 1 (TOP1) activity in different cell subpopulations, and the consequences for the chemotherapeutic response towards the TOP1 targeting drug, camptothecin. The cell lines consisted of two subpopulations: one (the stem-cell-like cells) divided asymmetrically, was camptothecin resistant, had a differently phosphorylated TOP1 and a lower Casein Kinase II (CKII) activity than the camptothecin sensitive non-stem-cell-like cells. The tumor suppressor p14ARF had a different effect in the two cell subpopulations. In the stem-cell-like cells, p14ARF suppressed TOP1 activity and downregulation of this factor increased the sensitivity towards camptothecin. It had the opposite effect in non-stem-cell-like cells. Since it is only the stem-cell-like cells that have tumorigenic activity our results point towards new considerations for future cancer therapy. Moreover, the data underscore the importance of considering cell-to-cell variations in the analysis of molecular processes in cell lines.
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