Environmental stresses induce karyotypic instability in colorectal cancer cells
| Autor: | Norman Pavelka, Giulia Rancati, Daniela Cimini, Zhihao Tan, Samuel D. Rutledge, Yong Jie Andrew Chan, Ying Jie Karen Chua |
|---|---|
| Přispěvatelé: | Biological Sciences, Fralin Life Sciences Institute |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Genome instability
Karyotype Mitosis Biology Environment Culture Media Serum-Free Chromosome segregation Polyploidy 03 medical and health sciences 0302 clinical medicine Stress Physiological Chromosome instability Cell Line Tumor Chromosome Segregation medicine Chromosomes Human Humans Molecular Biology Metaphase 030304 developmental biology Centrosome 0303 health sciences Cell Cycle Cancer Cell Biology Articles Hyperthermia Induced medicine.disease Cell Hypoxia 3. Good health Spindle checkpoint Mitotic exit Drug Resistance Neoplasm Cancer cell Cancer research M Phase Cell Cycle Checkpoints Colorectal Neoplasms 030217 neurology & neurosurgery |
| Zdroj: | Molecular Biology of the Cell |
| Popis: | Understanding how cells acquire genetic mutations is a fundamental biological question with implications for many different areas of biomedical research, ranging from tumor evolution to drug resistance. While karyotypic heterogeneity is a hallmark of cancer cells, few mutations causing chromosome instability have been identified in cancer genomes, suggesting a nongenetic origin of this phenomenon. We found that in vitro exposure of karyotypically stable human colorectal cancer cell lines to environmental stress conditions triggered a wide variety of chromosomal changes and karyotypic heterogeneity. At the molecular level, hyperthermia induced polyploidization by perturbing centrosome function, preventing chromosome segregation, and attenuating the spindle assembly checkpoint. The combination of these effects resulted in mitotic exit without chromosome segregation. Finally, heat- induced tetraploid cells were on the average more resistant to chemotherapeutic agents. Our studies suggest that environmental perturbations promote karyotypic heterogeneity and could contribute to the emergence of drug resistance. A*STAR Investigatorship [1437a00119]; National Science Foundation [MCB-1517506] We thank the Rancati and Pavelka labs for helpful discussions, Mathijs Voorhoeve for the pBabe-H2B-GFP plasmid, Graham Wright and members of the IMB Microscopy Unit for their assistance and advice, and Anna De Antoni from the FIRC Institute of Molecular Oncology for the coimmunoprecipitation advice. This study was funded by an A*STAR Investigatorship (Ref. No. 1437a00119) awarded to G.R. Work in the Cimini lab was partly supported by National Science Foundation grant MCB-1517506. |
| Databáze: | OpenAIRE |
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