Translationally controlled tumor protein is a target of tumor reversion.
By analyzing the gene expression profile between tumor cells and revertant counterparts that have a suppressed malignant phenotype, we previously reported a significant down-regulation of translationally controlled tumor protein (TCTP) in the revertants. In the present study, we derived, by using the H1 parvovirus as a selective agent, revertants from three major solid cancers: colon, lung, and melanoma cell lines. These cells have a strongly suppressed malignant phenotype both in vitro and in vivo. The level of TCTP is decreased in most of the revertants. To verify whether inhibition of TCTP expression induces changes in the malignant phenotype, in the classical, well established model of "flat reversion," v-src-transformed NIH3T3 cells were transfected with antisense TCTP. By inhibiting the expression of TCTP, the number of revertant cells was raised to 30%, instead of the reported rate for spontaneous flat revertants of 10(-6). Because TCTP encodes for a histamine-releasing factor, we tested the hypothesis that inhibitors of the histaminic pathway could be effective against tumor cells. We show that some antihistaminic compounds (hydroxyzine and promethazine) and other pharmacological compounds with a related structure (including thioridazine and sertraline) kill tumor cells and significantly decrease the level of TCTP. All together, these data suggest that, with tumor reversion used as a working model, TCTP was identified as a target and drugs were selected that decrease its expression and kill tumor cells.
Tuynder
Marcel
M
Molecular Engines Laboratories, 20 Rue Bouvier, 75011 Paris, France.
Fiucci
Giusy
G
Prieur
Sylvie
S
Lespagnol
Alexandra
A
Géant
Anne
A
Beaucourt
Séverine
S
Duflaut
Dominique
D
Besse
Stéphanie
S
Susini
Laurent
L
Cavarelli
Jean
J
Moras
Dino
D
Amson
Robert
R
Telerman
Adam
A
D000818:Animals; D001483:Base Sequence; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000473:pathology*; D010641:Phenotype; D014176:Protein Biosynthesis; D000090324:Tumor Protein, Translationally-Controlled 1
D017931:DNA Primers; D009363:Neoplasm Proteins; C000715647:TPT1 protein, human; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1