| Abstract: | 腎臟癌症狀出現較晚以及病徵難以察覺，又因腫瘤高度轉移的特性造成全身性轉移導致治療失效。因此持續研究天然物中尋找抗癌活性成份，以達到有效治療腎臟癌或作為輔助臨床標靶藥物使用，以期達到降低臨床藥物副作用，提升病患生活品質。知母皂苷AIII (Timosaponin AIII, TSAIII)是一種類固醇皂素(steroidal-saponin)，主要存在於百合科植物知母(Anemarrhena asphodeloides Bunge)根莖部，具有抗血栓形成以及抗癌作用，但TSAIII對於人類腎臟癌細胞的抗癌機制仍不清楚。本研究主要目的是探討TSAIII對於腎臟癌細胞抗癌效果以及其相關分子機轉。首先，以TSAIII處理人類腎臟癌細胞 (786-O、A-498和ACHN)，低劑量TSAIII並不會影響細胞的細存活率以及細胞週期分布。進一步分析發現TSAIII能有效抑制786-O以及A-498細胞移動以及侵襲能力，並減少Cathepsin C (CTSC)的蛋白表現。進一步以Western blot分析發現TSAIII誘導PTEN的表現量，並抑制PI3K/AKT訊息傳遞路徑。利用PI3K抑制劑 LY294002與TSAIII共同處理下，阻斷PI3K/AKT訊息傳遞路徑後會增強TSAIII抑制CTSC的表達，並且降低腎癌細胞的轉移能力。綜合以上結果發現TSAIII藉由抑制PI3K/AKT途徑以及其下游的CTSC表現，來達到抑制腎癌細胞的轉移。顯示TSAIII具有顯著的抗轉移活性，具有發展為腎臟癌抗癌藥物的潛在價值。
According to the Ministry of Health and Welfare, cancer still has been the top death cause in 2017. Renal cell carcinoma (RCC) is the most common type of kidney tumor in an adult. In addition, those with advanced cancer whose disease progresses despite standard therapy, treatment options are limited and survival is poor. In recent years, natural food extraction has been studied to have many biological activities, and can be used as cancer prevention and adjuvant treatment of cancer. In previous studies indicated that Timosaponin AIII (TSAIII), is a steroidal-saponin extract from the root and stem of Anemarrhena asphodeloides Bunge, has multiple bio-functions such as anti-bacterial, anti-allergic, anti-thrombosis, and potent anti-tumor activity. In this study, we explored the anti-tumor activity and molecular mechanism of TSAIII in RCC cells. Our finding indicated the cell viability and cell cycle distribution of 786-O, A-498 and ACHN were insignificantly influenced by TSAIII treatment. Moreover, TSAII inhibited migration and invasion of 786-O and A-498 cells, as well as significantly decreased expression of cathepsin C (CTSC) in both the cell types. Western blot analysis exhibited that PI3K/AKT activation was inhibited, but PTEN expression was increased, in response to TSAIII treatments. Combining TSAIII and PI3K inhibitors (LY294002), LY294002 synergically reduced the migration and invasion of 786‐O and A‐498 cells by TSAIII, as well as decreased the CTSC expression. In conclusion, TSAIII inhibits the metastatic properties of RCC cells via inhibiting PI3K/AKT cascade and the subsequent down-regulation of CTSC. Based on the above, TSAII may be a potential could be developed as an anti-metastatic agent for RCC. |
