| Summary: | 碩士 === 國立交通大學 === 分子醫學與生物工程研究所 === 98 === The epidermal growth factor receptor (EGFR) belongs to the ErbB/HER family of tyrosine kinase receptors. The activation of EGFR is important for promoting tumor growth. Gefitinib (Iressa™, ZD1839), a small molecule tyrosine kinase inhibitor, has been demonstrated the promising antitumor activity. It targets the catalytic domain of EGFR to compete with the ATP binding site. However, the precise EGFR-independent apoptotic mechanisms by gefitinib remain incompletely clear. In this study, we investigated the effects of gefitinib on the EGFR-independent cell death signaling pathways in human cancer cells. Direct cytotoxicity was observed in RKO (colon cancer), A549 (lung cancer), BFTC905 (bladder cancer), MCF7 (breast cancer) and
A375 (skin cancer) cells by gefitinib. The order of cytotoxic sensitivity was A375 > MCF7 > BFTC905 > A549 > RKO cells following treatment with 10-60 μM gefitinib for 24 h. Interestingly, A375, MCF7 and RKO cells expressed very low protein level of the phosphorylated-EGFR and total EGFR; in contrast, BFTC905 and A549 cells expressed the high level. Moreover, treatment with gefitinib induced apoptosis in A375 and BFTC905 cells. Securin, also known as pituitary tumor-transforming gene (PTTG), overexpresses in a variety of tumors and promotes tumorigenesis. We also observed that gefitinib inhibited the securin protein expression in cancer cells. Furthermore, loss of securin enhanced the gefitinib-induced cell death; conversely, an overexpression of securin resisted the gefitinib-induced cell death. Activating transcription factor 3 (ATF3), a transcription factor, may regulate the delicate balance between proliferative and apoptotic signals that control the development of cancer. We found that gefitinib induced ATF3 protein expression and translocated to nuclei. As a whole, we suggest that gefitinib can induce apoptosis that may be through the EGFR-independent pathways in cancer cells. Understanding the mechanisms which securin and ATF3
signal transduction on the regulation of apoptosis following treatment with gefitinib may contribute to the novel therapeutic strategies in cancers.
|
|---|
