UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner Journal Article
| Authors: | Hsueh, C. T.; Kelsen, D.; Schwartz, G. K. |
| Article Title: | UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner |
| Abstract: | UCN-01, a protein kinase C/cyclin-dependent kinase inhibitor, suppressed thymidylate synthase (TS) protein expression in a dose-dependent manner with near complete suppression at 1 mu m after a 24-h exposure in human gastric cancer cell line SK-GT5. Other protein kinase C/cyclin-dependent kinase inhibitors, including flavopiridol and safingol, had a similar effect on TS protein expression, but to a lesser degree. Moreover, UCN-01 repressed the induction of TS after 5-fluorouracil (FU) exposure by 90-95% and significantly enhanced the induction of apoptosis by FU from 4-8% with either FU or UCN-01 alone to 46 +/- 1% (P < 0.005 versus either single drug, reverse sequence, or the combination) when UCN-01 was given after FU, The effect of UCN-01 on TS was associated with a dose dependent suppression of the E2F-1 protein, a transcriptional activator of TS, Northern blot analysis revealed that TS mRNA levels decreased gradually as the concentration of UCN-01 increased, but that E2F-1 mRNA levels remained relatively unchanged, UCN-O1 may provide a novel way to enhance cellular sensitivity toward FU by means of suppressing TS expression mediated mainly by down-regulation of E2F-1. |
| Keywords: | protein; proliferation; resistance; cell-lines; pathway; degradation; agents; predicts; quantitation; e2f |
| Journal Title: | Clinical Cancer Research |
| Volume: | 4 |
| Issue: | 9 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 1998-09-01 |
| Start Page: | 2201 |
| End Page: | 2206 |
| Language: | English |
| ACCESSION: | WOS:000075742000025 |
| PROVIDER: | wos |
| PUBMED: | 9748140 |
| Notes: | Article -- Source: Wos |
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