Journal Article

Overexpression of thymosin β-4 renders SW480 colon carcinoma cells more resistant to apoptosis triggered by FasL and two topoisomerase II inhibitors via downregulating Fas and upregulating Survivin expression, respectively

Hung-Liang Hsiao, Wei-Shu Wang, Po-Min Chen and Yeu Su

in Carcinogenesis

Volume 27, issue 5, pages 936-944
Published in print May 2006 | ISSN: 0143-3334
Published online December 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi316

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The present work was conducted to further examine the effects of thymosin β-4 (Tβ4) upregulation on the apoptosis of SW480 colon cancer cells induced by T cells and various chemotherapeutic agents because reduced susceptibility to the cytotoxicity of an anti-Fas IgM (CH-11) in Tβ4-overexpressing cells has previously been reported by us. As expected, Tβ4 overexpressers were also more resistant to the killing effect of FasL-bearing Jurkat T cells. On the other hand, pretreating these cells with an MMP inhibitor restored not only their Fas levels but also their sensitivity to CH-11, suggesting a pivotal role of MMP in downregulating Fas in Tβ4 overexpressers. Interestingly, while the susceptibilities of Tβ4 overexpressers to 5-FU and irinotecan remained unchanged, they were more resistant to doxorubicin and etoposide which triggered apoptosis via a mitochondrial pathway. Concordantly, activation of both caspases 9 and 3 in Tβ4 overexpressers by the two aforementioned topoisomerase II inhibitors was dramatically abrogated which could be accounted mainly by an increased expression of Survivin, a critical anti-apoptotic factor. Finally, poor survival was found in stage III colon cancer patients whose tumors were stained positively by the anti-Survivin antibody. Thus, advantages such as immune evasion and resistance to anticancer drug-induced apoptosis acquired by colon cancer cells through Tβ4 overexpression might facilitate their survival during metastasis and chemotherapy.

Keywords: CRC, colorectal carcinoma; CTLs, cytotoxic T lymphocytes; cyt c, cytochrome c; DR, death receptor; FasL, Fas ligand; IHC, Immunohistochemical; LAK, lymphokine-activated killer; MMP, matrix metalloprotease; MTT assay, 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyl-2H tetrazolium bromide assay; NK, natural killer; NSAIDs, non-steroidal anti-inflammatory drugs; Tβ4, thymosin β-4; TRAIL, TNF-related apoptosis-inducing ligand

Journal Article.  6402 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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