N-Methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA
<p>Abstract</p> <p>Background</p> <p>Cellular senescence is a state in which mammalian cells enter into an irreversible growth arrest and altered biological functions. The senescence response in mammalian cells can be elicited by DNA-damaging agents. In the present stud...
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| Format: | Article |
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BMC
2004-01-01
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| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/3/1/3 |
| _version_ | 1818347808010272768 |
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| author | Narayan Satya Pathak Sen Multani Asha S Jaiswal Aruna S |
| author_facet | Narayan Satya Pathak Sen Multani Asha S Jaiswal Aruna S |
| author_sort | Narayan Satya |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Cellular senescence is a state in which mammalian cells enter into an irreversible growth arrest and altered biological functions. The senescence response in mammalian cells can be elicited by DNA-damaging agents. In the present study we report that the DNA-damaging agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is able to induce senescence in the HCT-116 colon cancer cell line.</p> <p>Results</p> <p>Cells treated with lower concentrations of MNNG (0–25 microM) for 50 h showed a dose-dependent increase in G<sub>2</sub>/M phase arrest and apoptosis; however, cells treated with higher concentrations of MNNG (50–100 microM) showed a senescence-like G<sub>0</sub>/G<sub>1 </sub>phase arrest which was confirmed by increased expression of β-galactosidase, a senescence induced marker. The G<sub>2/</sub>M phase arrest and apoptosis were found to be associated with increased levels of p53 protein, but the senescence-like G<sub>0</sub>/G<sub>1 </sub>phase arrest was dissociated with p53 protein levels, since the p53 protein levels decreased in senescence-like arrested cells. We further, determined whether the decreased level of p53 was a transcriptional or a translational phenomenon. The results revealed that the decreased level of p53 protein in senescence-like arrested cells was a transcriptional phenomenon since <it>p53 </it>mRNA levels simultaneously decreased after treatment with higher concentrations of MNNG. We also examined the effect of MNNG treatment on other cell cycle-related proteins such as p21, p27, cyclin B1, Cdc2, c-Myc and max. The expression levels of these proteins were increased in cells treated with lower concentrations of MNNG, which supported the G<sub>2</sub>/M phase arrest. However, cells treated with higher concentrations of MNNG showed decreased levels of these proteins, and hence, may not play a role in cell cycle arrest. We then examined a possible association of the expression of APC protein and telomeric DNA signals with cellular senescence in MNNG-treated cells. We found that protein and mRNA levels of <it>APC </it>were drastically reduced in cells treated with higher concentrations of MNNG. The loss of <it>APC </it>expression might lead to chromosomal instability as well as microtubular disorganization through its dissociation with tubulin. In fact, the protein level of α-tubulin was also drastically decreased in senescence-like arrested cells treated with higher concentrations of MNNG. The levels of telomeric DNA also decreased in cells treated with higher concentrations of MNNG.</p> <p>Conclusions</p> <p>These results suggest that in response to DNA alkylation damage the senescence-like arrest of HCT-116 cells was associated with decreased levels of APC protein, microtubular organization, and telomeric DNA.</p> |
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| id | doaj.art-291e7fe8e31047fa85d19b729fa4cd95 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-13T17:40:02Z |
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| series | Molecular Cancer |
| spelling | doaj.art-291e7fe8e31047fa85d19b729fa4cd952022-12-21T23:36:48ZengBMCMolecular Cancer1476-45982004-01-01313N-Methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNANarayan SatyaPathak SenMultani Asha SJaiswal Aruna S<p>Abstract</p> <p>Background</p> <p>Cellular senescence is a state in which mammalian cells enter into an irreversible growth arrest and altered biological functions. The senescence response in mammalian cells can be elicited by DNA-damaging agents. In the present study we report that the DNA-damaging agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is able to induce senescence in the HCT-116 colon cancer cell line.</p> <p>Results</p> <p>Cells treated with lower concentrations of MNNG (0–25 microM) for 50 h showed a dose-dependent increase in G<sub>2</sub>/M phase arrest and apoptosis; however, cells treated with higher concentrations of MNNG (50–100 microM) showed a senescence-like G<sub>0</sub>/G<sub>1 </sub>phase arrest which was confirmed by increased expression of β-galactosidase, a senescence induced marker. The G<sub>2/</sub>M phase arrest and apoptosis were found to be associated with increased levels of p53 protein, but the senescence-like G<sub>0</sub>/G<sub>1 </sub>phase arrest was dissociated with p53 protein levels, since the p53 protein levels decreased in senescence-like arrested cells. We further, determined whether the decreased level of p53 was a transcriptional or a translational phenomenon. The results revealed that the decreased level of p53 protein in senescence-like arrested cells was a transcriptional phenomenon since <it>p53 </it>mRNA levels simultaneously decreased after treatment with higher concentrations of MNNG. We also examined the effect of MNNG treatment on other cell cycle-related proteins such as p21, p27, cyclin B1, Cdc2, c-Myc and max. The expression levels of these proteins were increased in cells treated with lower concentrations of MNNG, which supported the G<sub>2</sub>/M phase arrest. However, cells treated with higher concentrations of MNNG showed decreased levels of these proteins, and hence, may not play a role in cell cycle arrest. We then examined a possible association of the expression of APC protein and telomeric DNA signals with cellular senescence in MNNG-treated cells. We found that protein and mRNA levels of <it>APC </it>were drastically reduced in cells treated with higher concentrations of MNNG. The loss of <it>APC </it>expression might lead to chromosomal instability as well as microtubular disorganization through its dissociation with tubulin. In fact, the protein level of α-tubulin was also drastically decreased in senescence-like arrested cells treated with higher concentrations of MNNG. The levels of telomeric DNA also decreased in cells treated with higher concentrations of MNNG.</p> <p>Conclusions</p> <p>These results suggest that in response to DNA alkylation damage the senescence-like arrest of HCT-116 cells was associated with decreased levels of APC protein, microtubular organization, and telomeric DNA.</p>http://www.molecular-cancer.com/content/3/1/3 |
| spellingShingle | Narayan Satya Pathak Sen Multani Asha S Jaiswal Aruna S N-Methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA Molecular Cancer |
| title | N-Methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA |
| title_full | N-Methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA |
| title_fullStr | N-Methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA |
| title_full_unstemmed | N-Methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA |
| title_short | N-Methyl-N'-nitro-N-nitrosoguanidine-induced senescence-like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein, microtubule organization, and telomeric DNA |
| title_sort | n methyl n nitro n nitrosoguanidine induced senescence like growth arrest in colon cancer cells is associated with loss of adenomatous polyposis coli protein microtubule organization and telomeric dna |
| url | http://www.molecular-cancer.com/content/3/1/3 |
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