| 摘要: | 研究指出，腫瘤細胞中，訊息路徑的上游信號分子(如：Epidermal growth factor receptor、Row address strobe (Ras)、Serum creatinine (Scr) 或 phosphoinositide 3-kinase (PI3K) 會有過度表現的現象，會促使一些訊息路徑的活化，像Mitogen-Activated protein kinase (MAPK) 或Akt訊息路徑，導致癌細胞增生。文獻指出，BX795為PDK1抑制劑，會阻斷PDK1/Akt的訊息傳遞路徑，進而抑制乳癌和前列腺癌細胞的生長，此外，BX795也能抑制Aurora B、IκB Kinase ε (IKKε) 與TANK-binding kinase 1 (TBK1) 的蛋白活性，使得癌細胞生長與存活受影響。本論文將探討BX795是否會影響口腔癌細胞的生長及細胞週期的調控，首先測試BX795對於口腔癌細胞 (HSC3、SCC2095和SCC4) 的生長抑制，結果顯示，BX795會抑制口腔癌細胞的生長，48小時 IC50 值分別為2.0、2.2與6.5 μM。在 2 μΜ的BX795給予時，造成口腔癌細胞(SCC2095)細胞週期明顯停滯在G2/M期，且負面調控TBK1、Cyclin A、Cyclin B1、MPM2的蛋白表現及Akt、Cdc25C和Cdc2的磷酸化表現，並正面調控p21的表現。BX795也會促使procaspase 8、Caspase-9 與PARP蛋白活化，誘發細胞凋亡。以上結果顯示，BX795會誘使口腔癌細胞的細胞週期停滯與細胞凋亡的發生。
Research indicated that upstream signaling molecules (such as: Epidermal growth factor receptor, Row address strobe (Ras), Serum creatinine (Scr), or phosphoinositide 3-kinase (PI3K) of the signal pathway had overexpression in the tumor cells, and induced the activation of some signaling pathway, like the Mitogen-Activated protein kinase (MAPK) pathway or PDK1/Akt signaling pathway. These pathways lead to the activation of cancer cell proliferation. It has been reported that BX795, a PDK1 inhibitor blocked PDK1/Akt signaling in tumor cells and inhibited the growth of breast and prostate tumor cells in culture or induced apoptosis. Furthermore, BX795 is not only a PDK1 inhibitor, also inhibits Aurora B, IκB Kinase ε (IKKε), TANK-binding kinase 1 (TBK1) protein activity, decreasing effect of cancer cells growth and survival. In this study, the in vitro effects of BX795 were evaluated in HSC3, SCC2095, and SCC4 oral cancer cell lines, BX795 inhibited cell viability of HSC3, SCC2095, and SCC4 cells with IC50 of 2.0, 2.2, and 6.5 μM, respectively. It induced G2/M arrest in a dose dependent manner up to 2 μM. Mechanistic evidence indicates that BX795 downregulated the expression of TBK1、 Cyclin A、 Cyclin B1、 MPM2 and phosphorylation of Akt、 Cdc25C、 Cdc2, and upregulated the expression of p21. BX795 induced protein activation of procaspase 8, caspase-9 and PARP, and induced apoptosis. These above results indicated that BX795 induces cell cycle arrest and apoptosis in oral cancer cells. |
