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.
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.
Hsiao
Hung-Liang
HL
Institute of Pharmacology, College of Medicine, National Yang-Ming University, Shih-Pai, Taipei 11221, Taiwan, R.O. China.
Wang
Wei-Shu
WS
Chen
Po-Min
PM
Su
Yeu
Y
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)
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