TRF2 inhibition triggers apoptosis and reduces tumourigenicity of human melanoma cells.
The inhibition of the telomere-binding protein TRF2, by expressing the dominant negative form TRF2(DeltaBDeltaC), has been used as a model of anti-telomere strategy to induce a reversion of the malignant phenotype of M14 and JR5 human melanoma lines. Over-expression of TRF2(DeltaBDeltaC) induced apoptosis and reduced tumourigenicity exclusively in JR5 cells. p53 and Rb status and apoptotic response to DNA damage did not seem to account for the different response of the two lines to TRF2 inhibition. Interestingly, JR5 cells possess shorter and more dysfunctional telomeres compared to M14 line. Moreover, the treatment with the G-quadruplex-interacting agent (G4-ligand) RHPS4 sensitises M14 cells to TRF2 inhibition. These results demonstrate that TRF2 can impair tumuorigenicity of human cancer cells. They further suggest that a basal level of telomere instability favours an efficient response to TRF2 inhibition and that a combined anti-TRF2 and G4-ligand therapy would have synergistic inhibitory effects on tumour cell growth.
Biroccio
Annamaria
A
Experimental Chemotherapy Laboratory, Experimental Research Centre, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, Rome 00158, Italy. biroccio@ifo.it
Rizzo
Angela
A
Elli
Raffaella
R
Koering
Catherine-Elaine
CE
Belleville
Aurélie
A
Benassi
Barbara
B
Leonetti
Carlo
C
Stevens
Malcolm F G
MF
D'Incalci
Maurizio
M
Zupi
Gabriella
G
Gilson
Eric
E
D017209:Apoptosis / Q000502:physiology*; D015139:Blotting, Southern; D015153:Blotting, Western; D005822:Genetic Vectors; D006801:Humans; D008545:Melanoma / Q000473:pathology* / Q000628:therapy; D009368:Neoplasm Transplantation; D016615:Telomere / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53