Reconstitution of hTERT restores tumorigenicity in melanoma-derived c-Myc low-expressing clones.
c-Myc is involved in the control of telomerase activity through its ability to induce the expression of the catalytic subunit of the enzyme, the human telomerase reverse transcriptase (hTERT). Our aim was to study whether telomerase plays a critical role in c-Myc-dependent tumorigenicity of melanoma cells. By using M14-derived clones, expressing low levels of c-Myc, we demonstrated that the down-regulation of c-Myc reduced cell proliferation rate, cloning efficiency and tumorigenicity and increased the apoptotic rate. Decreased tumorigenic potential correlated with reduced hTERT gene expression, telomerase activity and telomere shortening. Introduction of wild-type hTERT into these cells increased their proliferation rate and partially re-established their tumorigenic potential, at early passages, even though the apoptotic rate of the population remained unaltered. After several in vitro passages, hTERT-mediated cell proliferation made the tumorigenic potential of the c-Myc low-expressing clones comparable to that of the M14 parental line. Over-expression of the mutant biologically inactive hTERT did not drive cells to proliferate. In conclusion, our results demonstrate that the reconstitution of high levels of telomerase activity reverses the low tumorigenicity due to low c-Myc expression.
Biroccio
Annamaria
A
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy.
Amodei
Sarah
S
Benassi
Barbara
B
Scarsella
Marco
M
Cianciulli
Anna
A
Mottolese
Marcella
M
Del Bufalo
Donatella
D
Leonetti
Carlo
C
Zupi
Gabriella
G
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D019098:Telomerase / Q000235:genetics / Q000502:physiology*; D016615:Telomere / Q000648:ultrastructure; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D014410:Tumor Stem Cell Assay
D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D019098:Telomerase