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標題: 靈菌紅素在人類肺腺癌細胞中藉由抑制SKP2促進p27KIP1的蛋白穩定性造成細胞生長停滯
Prodigiosin induces p27KIP1 stabilization and growth inhibition by down-regulating SKP2 in human lung adenocarcinoma cells
作者: 謝欣穎
Hsieh, Hsin-Ying
關鍵字: Prodigiosin;靈菌紅素;lung adenicarcinoma;肺腺癌
出版社: 生物醫學研究所
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肺癌是目前被認為是一種轉移性強而且預後差的癌症,許多研究都積極的尋找有效的治療方法。PG是由細菌所產生的一種紅色色素,被認為是具有潛力的抗癌藥物,不過PG抑制癌細胞增生的機制目前還有待釐清。在本實驗中,我們發現PG處理可以藉由提升p27 kip1的表現有效抑制肺腺癌細胞的細胞週期進行,而且p27 kip1蛋白量的增加不是由於p27 kip1基因的高度表現,而是因為增加了p27 kip1在細胞內的蛋白穩定性。SKP2是一種E3 ubiquitin ligase的重要組成蛋白,被認為與p27 kip1的分解有直接關聯,的確PG處理後就會抑制SKP2的表現量。透過細胞群落分析,看到穩定抑制p27 kip1或是高度表現SKP2的細胞便不會受到PG抑制細胞增生效果的影響。最後,我們發現PG會透過調控PI3K/AKT/GSK-3b訊息路徑去抑制SKP2的表現,如果持續性活化AKT或共同處理GSK-3b抑制劑,會使PG降低SKP2蛋白的程度有回復現象。綜合以上結果,證實PG會抑制PI3K/AKT/GSK-3b這條訊息傳遞路徑去負調控SKP2的表現,因此使p27 kip1的蛋白穩定性提升進而導致細胞週期停滯抑制癌細胞增生,也顯示了在PG的抗癌機制中,SKP2扮演了連結上下游的重要角色,抑制此致癌基因有潛力成為未來治療肺癌的有效策略。

Lung cancer has been viewed as an aggressive disease with few treatment options and poor survival. Therefore, novel treatment strategies are needed. The anticancer agent prodigiosin (PG) is a natural red pigment produced by microorganisms. In this study, we demonstrated PG could lead to cell cycle arrest by increasing p27Kip1 expression in human lung adenocarcinoma cells. RT-PCR analysis, promoter activity assay and cycloheximide co-treatment indicated that the increased level of p27Kip1 was not due to increased p27Kip1 gene expression, but rather resulting from increased p27Kip1 protein stability. Intriguingly, SKP2, a central E3 ubiquitin ligase responsible for p27Kip1 degradation, was found to be markedly down-regulated by PG. Further analysis indicated that PG inhibits the SKP2 mRNA expression and promoter activity. Importantly, colony formation assay demonstrated that cells with stable p27Kip1 knockdown or ectopic SKP2 expression confer resistance to PG-induced antiproliferation. Finally, we found that PG regulates PI3K/AKT/GSK-3b signaling to down-regulate SKP2. Expression of constitutively active AKT or treatment with AR-A014418 could reverse the inhibition of SKP2 caused by PG. Together, these results indicates that PG inhibits PI3K/AKT/GSK-3b signaling to reduce SKP2 expression, which contributes to the increasing p27Kip1 stabilization therefore blocks the cell cycle progression. It also demonstrates that SKP2 is an important target of PG and give a potential strategy for chemotherapy in lung cancer.
其他識別: U0005-1608201117182700
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