近年, 制がん剤耐性を獲得した悪性がん細胞ではEMTが誘導されていることが報告されているが, そのEMT誘導メカニズムについては不明な点が多く残っていた。本研究ではまずシスプラチン持続暴露によってEMTが誘導されたがん細胞を樹立することに成功した。さらに樹立した細胞に対し, ケミカルゲノミクスの手法を用いて以下の事を明らかにした。すなわち, 制がん剤耐性の獲得に伴うEMT誘導のメカニズムの一つとして, シスプラチンを添加することでTGF-β産生の増加によるTGF-βシグナルが亢進し, これによってEMTが誘導, そして制がん剤耐性を獲得する, というモデルを提唱した。
There are now growing evidences suggesting an association between EMT, a hallmark of tumor malignancy, and chemoresistance to many cytotoxic drugs. However, it has not been fully clear about its mechanism. Here, we established cisplatin-resistant clones of human colorectal carcinoma LoVo cells (CDDPr/LoVo cells) by continuously exposing LoVo cells to cisplatin and we found that EMT was induced in CDDPr/LoVo cells. Thus, we performed chemical genomics approach to address the mechanism by which EMT was induced in CDDPr/LoVo cells. As a result, we found that the secretion of TGF-β in CDDPr/LoVo cells was elevated compared to that in LoVo cells. Moreover, when cisplatin was treated with LoVo cells, the secretion of TGF-β was enhanced within a few days after cisplatin treatment, which resulted in EMT induction. Since mesenchymal cells were resistance against cisplatin-induced apoptosis, it is likely that cisplatin-induced EMT by TGF-β secretion contributes to acquire the chemoresistance.
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