Decreased expression of hMLH1 correlates with reduced 5-fluorouracil-mediated apoptosis in colon cancer cells.

Decreased expression of hMLH1 correlates with reduced 5-fluorouracil-mediated apoptosis in colon cancer cells. Research Abstract Details 

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Decreased expression of hMLH1 correlates with reduced 5-fluorouracil-mediated apoptosis in colon cancer cells. Abstract Text:

Hideyuki Fujita,Jun Kato,Joichiro Horii,Keita Harada,Sakiko Hiraoka,Hidenori Shiraha,Kohsaku Sakaguchi,Yasushi Shiratori,Hideyuki Fujita,Jun Kato,Joichiro Horii,Keita Harada,Sakiko Hiraoka,Hidenori Shiraha,Kohsaku Sakaguchi,Yasushi Shiratori,

Patients with sporadic microsatellite instable colorectal cancers, in most of which the function of the hMLH1 mismatch repair gene is impaired, do not gain a survival benefit from 5-fluorouracil (5-FU)-based chemotherapy. However, the effect of hMLH1 on the cytotoxicity induced by 5-FU has not yet been sufficiently confirmed. In this study, we assessed the effect of hMLH1 on cytotoxicity and apoptosis induced by 5-FU using newly developed cell lines. We constructed two cell lines: SW480 (originally hMLH1-proficient), in which the expression of hMLH1 was reduced using a small interfering RNA (siRNA) technique, and HCT116 (originally hMLH1-deficient), in which the expression of hMLH1 can be regulated by doxycycline. Using these cell lines, a clonogenic survival assay, 4',6-diamidino-2-phenylindole (DAPI) staining and an Annexin-V assay were performed. Moreover, the incorporation of 5-FU into DNA was determined using tritium-labeled 5-FU. In both of our two cell lines, hMLH1-deficient cells exhibited approximately 2.4-fold clonal surviving fraction compared to hMLH1-proficient cells for 10 days after the administration of 5-FU. Additionally, hMLH1-deficient cells treated with 5-FU exhibited 34-45% less apoptosis than hMLH1-proficient cells according to the results of DAPI staining and Annexin-V assay. Furthermore, hMLH1-deficient cells treated with 5-FU exhibited an approximately 2-fold greater incorporation of 5-FU into DNA than control cells, suggesting that the recognition of 5-FU-incorporated DNA is impaired in hMLH1-deficient cells, resulting in reduced apoptosis. Our conclusions were that decreased expression of hMLH1 in colon cancer cells reduced the apoptosis induced by 5-FU, suggesting that hMLH1 is a key determinant of 5-FU chemosensitivity.

Decreased expression of hMLH1 correlates with reduced 5-fluorouracil-mediated apoptosis in colon cancer cells. Publishing Authors By Initials

H Fujita,J Kato,J Horii,K Harada,S Hiraoka,H Shiraha,K Sakaguchi,Y Shiratori,H Fujita,J Kato,J Horii,K Harada,S Hiraoka,H Shiraha,K Sakaguchi,Y Shiratori,

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Decreased expression of hMLH1 correlates with reduced 5-fluorouracil-mediated apoptosis in colon cancer cells. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Oncology reports

VOLUME: 18

Page Numbers: 1129-37

Journal Abbreviation: Oncol. Rep.

ISSN: 1021-335X

DAY: 4

MONTH: Nov

YEAR: 2007

Decreased expression of hMLH1 correlates with reduced 5-fluorouracil-mediated apoptosis in colon cancer cells. Information

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LANGUAGE: eng

NlmUniqueID: 9422756

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Grant and Affiliation Information for Decreased expression of hMLH1 correlates with reduced 5-fluorouracil-mediated apoptosis in colon cancer cells.

AFFILIATION: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

Country: Greece

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MEDLINETA: Oncol Rep

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