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

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.

Transcriptome profiling of malignant transformed rat hepatic stem-like cells by aflatoxin B1

“…High expression of Tmsb4x has been implicated in multiple cancers, including HCC [25]. Tmsb4x overexpression further rendered cancer cells more resistance to apoptosis triggered by FasL [26]. Consistent with this, Tmsb4x expression was more elevated as exposure dose increasing, up to 79-fold in the highest dose.…”

Colorectal carcinoma: from tumorigenesis to treatment

“…Another possible explanation for the positive correlation between Tb 4 expression and distant metastasis of CRC is increased expression of Survivin, an antiapoptotic factor [80,81]. Upregulation of Survivin is not only associated with poor prognosis of stage II [82] and III [unpublished data] CRC patients, but it also confers drug resistance (doxorubicin and etoposide) to Tb 4 -overexpressing colon cancer cells [83]. With the successful cloning of the functional human Tb 4 gene and delineation of its promoter [84], dissecting the molecular mechanism of aberrant Tb 4 expression during the metastatic progression of CRC became feasible.…”

Thymosin beta 4 is overexpressed in human pancreatic cancer cells and stimulates proinflammatory cytokine secretion and JNK activation

“…The acquired resistance to apoptosis by colon cancer cells through Tβ4 overexpression might facilitate their survival during metastasis and chemotherapy. 7 The expression of Tβ4 in mouse fibrosarcoma cells was also found to correlate with tumorigenicity and metastatic potential. Up-regulation of Tβ4 in weakly tumorigenic and nonmetastatic QR-32 cells (32-S) converted the cells to develop tumors and formed lung metastases in mice.…”

“…[6][7][8][9][10] SW 480 colon cancer cells overexpressing Tβ4 were more resistant to apoptosis induced by T cells and chemotherapeutic agents. The acquired resistance to apoptosis by colon cancer cells through Tβ4 overexpression might facilitate their survival during metastasis and chemotherapy.…”