砷化物是已知的致癌物，卻也有效用來治療許多的疾病，包括急性前骨髓性白血病、癌症和皮膚疾病。然而至今對於砷化物的致癌與治療效果的機轉仍未完全釐清。在我們實驗室之前的研究中，已經證實了三氧化二砷 (Arsenic trioxide, ATO) 會誘導 JNK 訊息傳遞路徑，進一步 N端 (63/73) 磷酸化的 c-Jun 會與 TGIF/HDAC1 結合，抑制 p21WAF1/CIP1 (p21) 基因的表現。但是 ATO 亦活化 Ras/Raf/ERK 訊息傳遞路徑，促進 c-Fos 蛋白表現而增加 p21 的表現。在本論文中，我們觀察到了給予較低劑量的 ATO 會增加細胞的生長，相反較高劑量則增加細胞的死亡在許多細胞株，如 A431、HaCaT、Huh7、MCF7 和 Hep3B 細胞。另外較高劑量的 ATO 能夠持續活化 ERK 訊息傳遞路徑，增加 c-Fos 蛋白而誘導 p21 的表現。此外我們也觀察到 ATO 可誘導 smad3 蛋白的磷酸化，smad3 的過度表現會增加 p21 促進子的活性，而且 ATO 誘導的 p21 表現會被 TGF-β type I receptor 抑制劑 SB431542 部分抑制。因此我們推測較高劑量 ATO 所誘導的持續 ERK 活化及 TGFβ/smad 訊息傳遞路徑可以拮抗 JNK 的作用，以誘導 p21 的活化。而且 ATO 合併處理 TSA (HDACs 抑制劑) 能夠協同性增加 p21 的表現及 A431 細胞的死亡。故我們推測 ATO 合併 TSA 或是 SP600125 (JNK 抑制劑) 或是將 TGIF 蛋白 knock-down，可能可以用來改善 ATO 在臨床上治療牛皮癬或癌症的效果。

Although arsenic is an infamous carcinogen, it has been effectively used to treat many ailments, including acute promyelocytic leukemia, solid tumors, and some skin diseases. So far, the mechanisms of the arsenic-induced carcinogenic or therapeutic effects are still poorly understood. Previously, we have demonstrated that ATO-induced JNK pathway can phosphorylate N-terminus of c-Jun (63/73) to recruit TGIF/HDAC1 to suppress p21WAF1/CIP1 (p21) expression, but the induced Ras/Raf/ERK pathway can enhance c-Fos expression to increase p21 expression. Presently, we observed that treatment with low doses of ATO can increase cell growth, but high doses of ATO can enhance cell death in A431, HaCaT, Huh7, MCF7, and Hep3B cell lines. In addition, high dose of ATO could sustain ERK activation, and then increase c-Fos protein to induce p21 expression. Furthermore, ATO-induced smad3 phosphorylation was also observed. Over-expression of smad3 could activate p21 promoter activity, and ATO-induced p21 expression could partially be inhibited by SB431542, TGFβ type I receptor inhibitor. Therefore, we suggest that sustained ERK activation and TGFβ/smad signaling in response to high dose of ATO could compete against JNK pathway and then induce p21 activation. Finally, ATO combined with TSA (a HDACs inhibitor) could synergistically enhance ATO alone induced p21 expression and subsequent cell death in A431 cells. We suggest that ATO combined with JNK inhibitor, or with HDAC1 inhibitor, or with knock-down of the TGIF expression could be used to improve the therapeutic effects of ATO in the clinical therapy of psoriasis or cancers.

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