Investigating the anti-tumor mechanism of carbazole derivatives

• Main Authors: Jing-Min Wang, 王經閔
• Other Authors: Jing-Jer Lin
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/92424991684246041065

碩士 === 國立陽明大學 === 生物藥學研究所 === 100 === G-quadruplex is a four-stranded DNA structure formed by G-rich sequence. Formation of G-quadruplex structure was shown to inhibit telomerase activity and affect gene expression at both transcription and translation levels. A G-quadruplex forming sequences was identified at the promoter of proto-oncogene Wnt-1. CD spectra analysis revealed that the sequence was capable of forming parallel form G-quadruplex. And NMR spectra also showed the sequence was capable of forming G-quadruplex stracture in the presence of potassium ion. The expressions of Wnt-1 upon G-quadruplex ligand treatments were first analyzed. We found two G-quadruplex stabilizers 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC) and 3,6-bis(4 -methyl-2-vinylpyrazinium iodine) carbazole (BMVC4) stabilized G-quadruplex structure by increasing the melting temperature by as many as ~20oC. Both BMVC and BMVC4 repressed the expression of Wnt-1 through stabilization of G-quadruplex structure at the promoter region. The reporter assay showed that BMVC and BMVC4 could inhibit Wnt-1 promoter expression. And next we found both BMVC and BMVC4 inhibited the expression of Wnt-1 downstream genes -catenin, Survivin and MMP-7. The cellular effects of BMVC and BMVC4 treatments were next determined. Consequently, BMVC and BMVC4 inhibited the migration and invasion abilities of cancer cells. Together our results support a novel mechanism that G-quadruplex stabilizers BMVC and BMVC4 inhibit cancer cell metastasis through repressing the expression of Wnt-1 expression.