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The Molecular Mechanisms and Biological Effects of AMPK Inhibitor–Compound C Induced Egr-1 Expression in Skin Cancer Cells
|關鍵字:||皮膚癌；立即性早期生長因子-1；腺苷磷酸活化激酶抑制劑;skin cancer；EGR-1；AMPK inhibitor-Compound C||出版社:||生命科學系所||引用:||參考文獻 1.Mariko Hara-Chikuma and A. S. Verkman. Prevention of Skin Tumorigenesis and Impairment of Epidermal Cell Proliferation by Targeted Aquaporin-3 Gene Disruption. Mol Cell Biol. 28(1): 326–332. (2008) 2.Takayuki Iriyama, et al. ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis. EMBO J. 28(7): 843–853. (2009) 3.McCormick JJ, Maher VM. Malignant transformation of human skin fibroblasts by two alternative pathways. Adv Exp Med Biol. 720: 191-207. (2011) 4.Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: incidence. J Am Acad Dermatol. 30: 774-8. (1994) 5.Cantwell MM, et al. Second primary cancers in patients with skin cancer: a population-based study in Northern Ireland. Br J Cancer. 100(1): 174-7. (2009) 6.Rogers HW, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. 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Compound C，為腺苷磷酸活化激酶 (AMPK, AMP-activated protein kinase) 抑制劑，於近來的研究顯示 : Compound C可以透過不依賴AMPK的方式而誘導不同癌細胞株進行凋亡與自噬。於實驗室先期研究中，以人類基底細胞癌細胞株 (BCC, Basal cell carcinoma) 為生物模式，證實Compound C能誘導BCC細胞株進行細胞凋亡與自噬反應，並誘導大量轉錄因子Egr-1 (Eearly growth response gene 1) 表現。目前已知，Egr-1參與調控細胞週期的進程 (cell cycle progression) 與存活 (survival)，但並未有研究顯示於皮膚癌細胞中受誘導而表現之Egr-1的功能，因此，本研究首先採用人類基底細胞癌細胞株 (BCC) 為主要生物模式，並探及其他皮膚癌細胞株進行討論，以釐清Compound C誘導皮膚癌細胞中轉錄因子Egr-1的分子表現機制以及其對皮膚癌細胞株存活率之影響。實驗中我們首先證實了Compound C的確可以誘導皮膚癌細胞中Egr-1之轉錄作用，而Egr-1啟動子上-714 ~ -552以及-550 ~ -403區段對誘導反應是重要的，在共軛焦顯微鏡的影像結果中則觀測到受誘導表現的EGR-1分子與核共位的現象。在分子機制的調控，我們證實 : ERK參與在Compound C所誘導Egr-1的轉錄作用中，並且NF-kB與PI3K亦促使EGR-1蛋白質表現量提升，但是PKA則間接透過抑制蛋白酶體的活性而負調控EGR-1的表現。在細胞株存活率的探討中，我們使用剔降細胞株BCC/shEGR-1進行實驗，證實剔降EGR-1分子會加劇Compound C所誘導BCC細胞株存活率的下降，並且Caspase3/7活性與細胞凋亡標的蛋白Cleaved Caspase-9 (Asp315)、Cleaved Caspase-3 (Asp175)、Cleaved PARP (Asp214) 表現量均有進一步提升的情形，顯示Compound C所誘導的EGR-1分子在皮膚癌細胞中具有抗凋亡之能力。於實驗中亦去檢測EGR-1分子在Compound C誘導BCC細胞進行自噬反應中的角色，由實驗結果顯示 : EGR-1分子不影響Compound C所誘發之自噬反應的產生。總結以上實驗結果與文獻，我們推論 : Compound C分子會誘導皮膚癌細胞進行凋亡與自噬反應，顯示，Compound C在皮膚癌治療上的潛力，而EGR-1分子或許可以做為皮膚癌治療上抗藥性 (chemotherapy resistant) 生成之指標。
Compound C is commonly used as an inhibitor of AMP-activated protein kinase (AMPK), which serves as a energy sensor in cells. It inhibits the activation of AMPK and lead to apoptotic cell death. Recently, Compound C was reported that could induce apoptotic and autophagic cell death in different cancer cell lines via AMPK- independent manner. In our preliminary results, Compound C promoted basal cell carcinoma cells (BCC) into apoptotic and autophagic cell death while Egr-1 (early growth response gene 1) gene expression was upregulated largely. Egr-1, a zinc-finger transcription factor, has been found participate in regulation of cell cycle progression and cell survival. In skin tumorigenesis, Egr-1 has been considered to be as a tumor suppressor gene. However, the role of Egr-1 induction in skin cancer cell lines by Compound C is still unknown. In this study, we used skin cancer cell lines as cell models to explore the molecular mechanism of Compound C-induced Egr-1 expression in skin cancer and the role of Egr-1 in Compound C-induced skin cancer cell death. First, we demonstrated that Compound C upregulated Egr-1 expression at transcriptional level in skin cancer cells via MEK/ERK pathway. The luciferase reporter assay delineated two region located at position -714/-552 and -550/-403 from transcription initiation start site were critical for Compound C-induced Egr-1 transcription. The NF-kB and PI3K/Akt signaling pathway also participated in the promotion of EGR-1 protein expression. Oppositely, PKA negatively regulated EGR-1 expression via enhancing the proteasome function. Confocal image data showed that the EGR-1 expression was co-localized with nuclei. In the survival rate assay, we observed that knockdown EGR-1 decreased the survival rate of BCC dramatically after Compound C treatment. The caspase3/7 activity and apoptotic marker expression were also increased in BCC/shEGR-1 cells by magic red staining assay and western bolt after treated with Compound C. However, we didn’t find any differences in LC3II protein expression between treated control cell and BCC/shEGR-1. According to the above results, we supposed that Compound C has a potential role in skin caner chemotherapy, and the molecular role of EGR-1 may antagonize the Compound C-induced pro-apoptotic cell death.
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