title: Overexpression of thymosin beta-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.
abstract: The present work was conducted to further examine the effects of thymosin beta-4 (Tbeta4) 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 Tbeta4-overexpressing cells has previously been reported by us. As expected, Tbeta4 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 Tbeta4 overexpressers. Interestingly, while the susceptibilities of Tbeta4 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 Tbeta4 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 Tbeta4 overexpression might facilitate their survival during metastasis and chemotherapy.
authors.affiliation: Institute of Pharmacology, College of Medicine, National Yang-Ming University, Shih-Pai, Taipei 11221, Taiwan, R.O. China.
authors.forename: Hung-Liang
authors.initials: HL
authors.lastname: Hsiao
authors.forename: Wei-Shu
authors.initials: WS
authors.lastname: Wang
authors.forename: Po-Min
authors.initials: PM
authors.lastname: Chen
authors.forename: Yeu
authors.initials: Y
authors.lastname: Su
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D020128:Inhibitory Concentration 50; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011379:Prognosis; D000077022:Survivin; D013947:Thymosin / Q000096:biosynthesis* / Q000502:physiology*; D013997:Time Factors; D059005:Topoisomerase II Inhibitors; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D019014:fas Receptor / Q000096:biosynthesis*; D000099201:Thymosin beta(4)
chemical_list: D020169:Caspases; D053222:Fas Ligand Protein; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D013947:Thymosin; D059005:Topoisomerase II Inhibitors; D048069:Tumor Necrosis Factors; D019014:fas Receptor; D000099201:Thymosin beta(4); C107489:BIRC5 protein, human; C505661:FASLG protein, human