| Summary: | 博士 === 國立陽明大學 === 生物藥學研究所 === 99 === Telomerase is the enzyme responsible for extending G-strand telomeric DNA and represents a promising target for neoplasia therapeutic treatments. Inhibition of telomerase can be achieved by stabilization of G-quadruplex DNA structures. Here we characterized the cellular effects of carbazole derivatives, 3,6-bis(1-methyl-4-
vinylpyridinium) carbazole diiodide (BMVC) and 3,6-bis(4 -methyl-2-vinylpyrazinium iodine) carbazole (BMVC4), that stabilized G-quadruplex DNA structure and inhibited telomerase activity. Each one of BMVC-treated or BMVC4-treated cancer cells was ceased to divide after a lag period and shown the hallmarks of senescence. Consistent with their role in inhibiting telomerase activity, the BMVC-induced or BMVC4-induced senescent phenotype are accompanied by progressive telomere shortening. Interestingly, BMVC suppressed the tumor-related properties of cancer cells including cell migration, colony-forming ability, and anchorage-independent growth and also reduced tumor growth in mouse xenografts, indicating that the cellular effects of BMVC did not limit on telomeres. Additionally, transcriptional analysis of BMVC4 -treated cancer cells showed that the expression of a proto-oncogene, c-myc, was inhibited through stabilization of the G-quadruplex structure located at the c-myc promoter. The expression of hTERT (the catalytic subunit of telomerase), a downstream target of c-myc, was also decreased with BMVC4-treatments. Surprisingly, the cellular effects of BMVC4 didn’t limited on telomeres. We found that BMVC4 induced senescent phenotypes in ALT (alternative lengthening of telomeres) cells. Moreover, DNA breaks were also detected in BMVC4-treated cells, the results suggest that the DNA damage response might be responsible for the telomere-independent senescence pathway. All together our analysis on BMVC and BMVC4 demonstrate that G-quadruplex stabilizers induce senescence in cancer cells through multiple pathways.
|
|---|
