RESUMO
Deregulation of tRNAs, aminoacyl-tRNA synthetases and tRNA modifying enzymes are common in cancer, raising the hypothesis that protein synthesis efficiency and accuracy (mistranslation) are compromised in tumors. We show here that human colon tumors and xenograft tumors produced in mice by two epithelial cancer cell lines mistranslate 2- to 4-fold more frequently than normal tissue. To clarify if protein mistranslation plays a role in tumor biology, we expressed mutant Ser-tRNAs that misincorporate Ser-at-Ala (frequent error) and Ser-at-Leu (infrequent error) in NIH3T3 cells and investigated how they responded to the proteome instability generated by the amino acid misincorporations. There was high tolerance to both misreading tRNAs, but the Ser-to-Ala misreading tRNA was a more potent inducer of cell transformation, stimulated angiogenesis and produced faster growing tumors in mice than the Ser-to-Leu misincorporating tRNA. Upregulation of the Akt pathway and the UPR were also observed. Most surprisingly, the relative expression of both misreading tRNAs increased during tumor growth, suggesting that protein mistranslation is advantageous in cancer contexts. These data highlight new features of protein synthesis deregulation in tumor biology.
Assuntos
Carcinoma , Códon , Neoplasias do Colo , Proteínas de Neoplasias , Proteoma , RNA Neoplásico , RNA de Transferência , Animais , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Embrião de Galinha , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Camundongos , Células NIH 3T3 , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteoma/biossíntese , Proteoma/genética , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , RNA de Transferência/genética , RNA de Transferência/metabolismoRESUMO
The expression of transfer RNAs (tRNAs) is deregulated in cancer cells but the mechanisms and functional meaning of such deregulation are poorly understood. The proteome of cancer cells is not fully encoded by their transcriptome, however, the contribution of mRNA translation to such diversity remains to be elucidated. We review data supporting the hypothesis that tRNA expression deregulation and translational error rate is an important contributor to proteome diversity and cell population heterogeneity, genome instability, and drug resistance in tumors. This hypothesis is aligned with recent data in various model organisms, showing unanticipated adaptive roles of translational errors (adaptive mistranslation), expression control of specific gene subsets by tRNAs, and proteome diversification by elevation of translational error rates in tumors.