scholarly journals Reduced ATR or Chk1 Expression Leads to Chromosome Instability and Chemosensitization of Mismatch Repair–deficient Colorectal Cancer Cells

2009 ◽  
Vol 20 (17) ◽  
pp. 3801-3809 ◽  
Author(s):  
Melanie J. Jardim ◽  
Qinhong Wang ◽  
Ryohei Furumai ◽  
Timothy Wakeman ◽  
Barbara K. Goodman ◽  
...  

Genomic instability in colorectal cancer is categorized into two distinct classes: chromosome instability (CIN) and microsatellite instability (MSI). MSI is the result of mutations in the mismatch repair (MMR) machinery, whereas CIN is often thought to be associated with a disruption in the APC gene. Clinical data has recently shown the presence of heterozygous mutations in ATR and Chk1 in human cancers that exhibit MSI, suggesting that those mutations may contribute to tumorigenesis. To determine whether reduced activity in the DNA damage checkpoint pathway would cooperate with MMR deficiency to induce CIN, we used siRNA strategies to partially decrease the expression of ATR or Chk1 in MMR-deficient colorectal cancer cells. The resultant cancer cells display a typical CIN phenotype, as characterized by an increase in the number of chromosomal abnormalities. Importantly, restoration of MMR proficiency completely inhibited induction of the CIN phenotype, indicating that the combination of partial checkpoint blockage and MMR deficiency is necessary to trigger CIN. Moreover, disruption of ATR and Chk1 in MMR-deficient cells enhanced the sensitivity to treatment with the commonly used colorectal chemotherapeutic compound, 5-fluorouracil. These results provide a basis for the development of a combination therapy for those cancer patients.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 683-683
Author(s):  
Taichi Isobe ◽  
Mark A. Zarnegar ◽  
Omar Ibrahim Abdel-Wahab ◽  
Michael F. Clarke

683 Background: Impaired cellular differentiation causes uncontrolled proliferation of stem cells and can be a cause of oncogenesis. The epigenome regulates the expression of genes that are essential for cellular differentiation. On the other hand, chromosomal abnormalities are common in colorectal cancer cells. We hypothesize that epigenetic disorders caused by chromosomal abnormalities may result in oncogenesis. Methods: The Cancer Genome Atlas (TCGA) database was investigated to identify epigenetic regulating genes affected by chromosomal abnormalities. Patient-derived colorectal cancer cells were obtained from consented patients to validate these findings. Results: The amplification of Chr20q11 is the most frequent chromosomal alteration in left-sided colonic and rectal cancers. ASXL1, a recruiter of PRC2, is coded in Chr20q11 and has upregulated expression in many cases. Excessive expression of ASXL1 may cause oncogenesis as PRC2 trimethylates histone H3 on lysine 27 (H3K27me3), an epigenetic mark of transcriptional silencing. Immunofluorescence revealed that the ASXL1 protein was located in the nuclei of colorectal cancer cells that did not express differentiation markers. This finding was consistent with the finding that ASXL1 highly expressed at the bottom of crypts where undifferentiated cells exist in normal colonic epithelium. Knockdown of ASXL1 in colorectal cancer cells reduced the levels of H3K27me3 and diminished organoid formation in vitro. Knockdown of ASXL1 in patient-derived cancer cells obtained from clinical specimens impaired the tumorigenicity of cancer initiating cells in vivo and increased the expression of differentiation markers. Murine colonic tumor cells from ApcMin mice highly expressed ASXL1, while homozygous Asxl 1 knockout reduced the occurrence of tumors in vivo. Many putative genes regulated by ASXL1 are identified by gene expression analysis and ChIP-sequencing. Conclusions: High expression of ASXL1 initiates oncogenesis and maintains the stemeness of colorectal cancer cells.


2015 ◽  
Vol 148 (3) ◽  
pp. 579-589 ◽  
Author(s):  
Stephanie S. Tseng-Rogenski ◽  
Yasushi Hamaya ◽  
Daniel Y. Choi ◽  
John M. Carethers

2011 ◽  
Vol 140 (5) ◽  
pp. S-97
Author(s):  
Heekyung Chung ◽  
Stephanie Tseng-Rogenski ◽  
Joy Chaudhry ◽  
Dennis J. Young ◽  
John M. Carethers

2019 ◽  
Vol 93 (8) ◽  
pp. 2265-2277 ◽  
Author(s):  
Maja T. Tomicic ◽  
Christian Steigerwald ◽  
Birgit Rasenberger ◽  
Anamaria Brozovic ◽  
Markus Christmann

2011 ◽  
Vol 301 (5) ◽  
pp. G929-G937 ◽  
Author(s):  
Zhiyun He ◽  
Dharmalingam Subramaniam ◽  
Satish Ramalingam ◽  
Animesh Dhar ◽  
Russell G. Postier ◽  
...  

DNA mismatch repair is required for correcting any mismatches that are created during replication and recombination, and a defective mismatch repair system contributes to DNA damage-induced growth arrest. The colorectal cancer cell line HCT116 is known to have a mutation in the hMLH1 mismatch repair gene resulting in microsatellite instability and defective mismatch repair. Honokiol is a biphenolic compound that has been used in traditional Chinese medicine for treating various ailments including cancer. This study was designed to test the hypothesis that honokiol enhances the radiosensitivity of cancer cells with mismatch repair defect (HCT116) compared with those that are mismatch repair proficient (HCT116-CH3). We first determined that the combination of honokiol and γ-irradiation treatment resulted in dose-dependent inhibition of proliferation and colony formation in both cell lines. However, the effects were more pronounced in HCT116 cells. Similarly, the combination induced higher levels of apoptosis (caspase 3 activation, Bax to Bcl2 ratio) in the HCT116 cells compared with HCT116-CH3 cells. Cell cycle analyses revealed higher levels of dead cells in HCT116 cells. The combination treatment reduced expression of cyclin A1 and D1 and increased phosphorylated p53 in both cell lines, although there were significantly lower amounts of phosphorylated p53 in the HCT116-CH3 cells, suggesting that high levels of hMLH1 reduce radiosensitivity. These data demonstrate that honokiol is highly effective in radiosensitizing colorectal cancer cells, especially those with a mismatch repair defect.


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