Regulation of normal and cancer cells as a base for cell cycle-targeted therapy
Author
Summary, in English
In these studies we used patient materials, cancer cell lines, and knockout and xenograft mouse models. We show that promoter methylation patterns are changed in several key genes, in particular p16 in leukemic cells compared to their normal counterparts, and that such epigenetic changes are also associated with treatment response to therapeutic drugs. Next, we show that cyclin A1 function is required for HSPC to home to and interact with niche regions under steady state condition and upon γ-irradiation treatment. The regulation of HSPC numbers and their interaction with the niches by cyclin A1 are critical for protection of the bone marrow from injury. We further show that the introduction of cyclin A1 overexpression promotes expansion of ALDH-positive population representing cancer stem cells in cell lines, increase their ability to form tumor spheres in vitro, and to metastasize in xenograft mice. Overexpression of cyclin A1 reduced sensitivity of ALDH-positive population within PCa cells to avastin and docetaxel combination treatment. Finally, we show that cyclin A1 associated CDK1 and its associated network proteins in particular RARγ are responsible for cell cycle progression through G0/G1 and G2/M phases. CDK1 and RARγ function are required to facilitate ATRA-effect on leukemic cells. Our findings unravel cellular mechanism underlying proliferation and survival of normal stem cells and cancer stem cells under steady state condition and upon treatment. Our novel findings shield light for designing novel treatment strategies to overcome drug-resistance of cancer cells.
Department/s
- Experimental Cancer Research, Malmö
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2013
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2013:91
Document type
Dissertation
Publisher
Department of Laboratory Medicine, Lund University
Topic
- Clinical Medicine
Keywords
- Cell cycle regulation
- cyclin A1
- stem cells
- stem cell niche
- epigenetics
- cancer
Status
Published
Research group
- Experimental Cancer Research, Malmö
Supervisor
- Jenny L Persson
- Anders Bredberg
- Anita Sjölander
- Anette Gjörloff Wingren
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87449-63-5
Defence date
12 September 2013
Defence time
13:00
Defence place
CRC Aula, Jan Waldenströms gata 35, ing 72, Malmö
Opponent
- David Heery (Professor)