Background:The Wnt1 pathway is recognized to play a major role in cancer progression. Results: The promoter region of the WNT1 gene can form G-quadruplex structures, which regulate WNT1 expression and its downstream signaling pathways. Conclusion: The Wnt1-mediated migration and invasion activities of cancer cells are inhibited by G-quadruplex stabilizers. Significance: A pathway-specific strategy is identified to repress cancer metastasis using G-quadruplex stabilizers.
Carbazole derivatives that stabilized G-quadruplex DNA structure formed by human telomeric sequence have been designed and synthesized. Among them, 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide (BMVC) showed an increase in G-quadruplex melting temperature by 13°C and has a potent inhibitory effect on telomerase activity. Treatment of H1299 cancer cells with 0.5 Mmol/L BMVC did not cause acute toxicity and affect DNA replication; however, the BMVC-treated cells ceased to divide after a lag period. Hallmarks of senescence, including morphologic changes, detection of senescence-associated B-galactosidase activity, and decreased bromodeoxyuridine incorporation, were detected in BMVC-treated cancer cells. The BMVCinduced senescence phenotype is accompanied by progressive telomere shortening and detection of the DNA damage foci, indicating that BMVC caused telomere uncapping after long-term treatments. Unlike other telomerase inhibitors, the BMVC-treated cancer cells showed a fast telomere shortening rate and a lag period of growth before entering senescence. Interestingly, BMVC also suppressed the tumor-related properties of cancer cells, including cell migration, colony-forming ability, and anchorage-independent growth, indicating that the cellular effects of BMVC were not limited to telomeres. Consistent with the observations from cellular experiments, the tumorigenic potential of cancer cells was also reduced in mouse xenografts after BMVC treatments. Thus, BMVC repressed tumor progression through both telomere-dependent and telomereindependent pathways. (Mol Cancer Res 2008;6(6):955 -64)
BACKGROUND AND PURPOSETelomerase is the enzyme responsible for extending G-strand telomeric DNA and represents a promising target for treatment of neoplasia. Inhibition of telomerase can be achieved by stabilization of G-quadruplex DNA structures. Here, we characterize the cellular effects of a novel G-quadruplex stabilizing compound, 3,6-bis(4-methyl-2-vinylpyrazinium iodine) carbazole (BMVC4).
EXPERIMENTAL APPROACHThe cellular effects of BMVC4 were characterized in both telomerase-positive and alternative lengthening of telomeres (ALT) cancer cells. The molecular mechanism of how BMVC4 induced senescence is also addressed.
KEY RESULTSBMVC4-treated cancer cells showed typical senescence phenotypes. BMVC4 induced senescence in both ALT and telomerase-overexpressing cells, suggesting that telomere shortening through telomerase inhibition might not be the cause for senescence. A large fraction of DNA damage foci was not localized to telomeres in BMVC4-treated cells and BMVC4 suppressed c-myc expression through stabilizing the G-quadruplex structure located at its promoter. These results indicated that the cellular targets of BMVC4 were not limited to telomeres. Further analyses showed that BMVC4 induced DNA breaks and activation of ataxia telangiectasia-mutated mediated DNA damage response pathway.
CONCLUSIONS AND IMPLICATIONSBMVC4, a G-quadruplex stabilizer, induced senescence by activation of pathways of response to DNA damage that was independent of its telomerase inhibitory activity. Thus, BMVC4 has the potential to be developed as a chemotherapeutic agent against both telomerase positive and ALT cancer cells.
AbbreviationsALT, alternative lengthening of telomeres; ATM, ataxia telangiectasia-mutated; ATR, ATM and Rad3-related; BMVC, 3,6-bis(1-methyl-4-vinylpyridium iodide) carbazole; BMVC4, 3,6-bis(4-methyl-2-vinylpyrazinium iodide) carbazole; hTERT, human telomerase reverse transcriptase; QFS, G-quadruplex forming sequences; SA-b-Gal, senescence-associated (SA) b-galactosidase BJP British Journal of Pharmacology
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