硒是一種必須不可缺少的元素，對我們的健康與疾病的發展具有重要的角色。一般認為，低濃度的硒容易在腫瘤前細胞或腫瘤細胞中轉變成促氧化劑，腫瘤細胞對硒的補充會比良性細胞更加敏感。Se化合物治療在多種癌症細胞中確切參與的分子靶標和機制仍未釐清。大腸癌是台灣近年來最常見的癌症之一，因此我們需要尋找有效的大腸癌化學療法。研究發現ROS可能藉由誘發基因突變，氧化還原相關的訊息傳導和氧化還原相關的轉錄因子參與結直腸癌的致癌過程。有趣的是，相關機制研究發現，隨著時間與劑量反應關係下，硒代胱氨酸會導致各種癌細胞增加細胞內ROS的產生。因此我們認為很值得研究L-selenocystine是否可作為有效的大腸癌化學療法並釐清其精確的藥物分子靶標和機制。其中，細胞自噬在癌症發生中具有雙重角色，它可以是腫瘤抑制因子或是腫瘤促進因子，許多研究發現細胞自噬作用在癌症治療過程的複雜性，其中可能參與細胞內氧化壓力，細胞死亡或發炎的重要作用，所以細胞自噬、ROS和發炎在腫瘤細胞中可能存在相互影響的關係。因此抗癌藥物針對細胞自噬的療法被認為可能是一種全新的癌症治療方法。我們初步的結果發現，L-selenocystine抑制了幾種細胞自噬相關蛋白的表現，並且引發細胞氧化壓力與多種發炎基因的表現。因此本研究計畫，我們想探討L-selenocystine對人類大腸癌上皮細胞的細胞自噬，氧化壓力和炎症反應之間相互關係的影響。 ;Selenium (Se) is an essential and unique trace element that plays a vital role in health and disease. It is generally believed that Se turn into a pro-oxidant at lower concentrations in preneoplastic or tumor cells than those of in benign cells, hence tumor cells are more sensitive to Se supplementation. However, the precise molecular targets and mechanisms engaged following Se compounds treatment in various cancer models not in normal cells are still inconclusive. In Taiwan, colorectal cancer is one of the greatest frequently diagnosed cancers in recent years. It is in urgent need of discovery effective chemotherapy for colorectal cancer. ROS may mediate the colorectal carcinogenesis through gene mutations, redox related signaling pathways and redox related transcription factors. Interestingly, mechanistic studies showed that selenocystine time- and dose-dependently increased intracellular reactive oxygen species (ROS) in various susceptible cancer cells. It is worth to investigate whether selenocompound (L-selenocystine) act as effective chemotherapy and clarify precise molecular targets and mechanisms in colorectal cancer. Autophagy plays a dual role in tumorigenesis, which act as both tumor suppressor and tumor promoter. It has been proposed for the complexity of autophagy effects during cancer therapy, which involving vital roles of ROS, cell death or inflammations. Autophagy, ROS and inflammations may exist mutual crosstalk in tumor cell. Anti-autophagy therapy is an entirely new approach to cancer treatment. Our preliminary results show that L-selenocystine inhibited several autophagy associated proteins expression. Oxidative stress and inflammations occur after L-selenocystine treatment. In this study, we would like to determine the effects of L-Selenocystine on mutual crosstalk between autophagy, oxidative stress and inflammatory responses in human colorectal adenocarcinoma cells.
