RESUMO
Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT), a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated ß-galactosidase activity, heterochromatin protein 1ß foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate cancer cells was under separate control. These data demonstrate a previously unrecognized link between inhibition of androgen receptor signaling, down-regulation of S-phase kinase-associated protein 2, and the appearance of secretory, tumor-promoting senescent cells in prostate tumors. We propose that ADT may contribute to the development of androgen-independent prostate cancer through modulation of the tissue microenvironment by senescent cells.
Assuntos
Antagonistas de Androgênios/farmacologia , Senescência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Proteínas Quinases Associadas a Fase S/metabolismo , Western Blotting , Catepsina B/metabolismo , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Masculino , Microscopia Confocal , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Interferência de RNA , Receptores Androgênicos/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Transdução de Sinais/efeitos dos fármacos , Vimentina/metabolismo , beta-Galactosidase/metabolismoRESUMO
BACKGROUND: Telomerase activity is associated with many malignancies, including head and neck cancer. The use of telomerase activity as a diagnostic and prognostic marker of head and neck cancer development was examined and compared with standard histological analysis. PATIENTS AND METHODS: Telomerase activity was determined using quantitative dual-colour real-time TRAP (telomeric repeat amplification protocol). In each of 58 patients, a sample of tumour tissue, adjacent mucosa and normal muscle was collected. RESULTS: Telomerase activation was observed in 88% of tumour tissues and 34% of tumour-adjacent mucosa samples. No telomerase activity was detected in normal muscle tissues. Telomerase activity correlated with tumour grade, with an average of 4.6 telomerase units (T.U.) in well-differentiated, 8.3 T.U. in moderately-differentiated and 20 T.U. in poorly differentiated tumours. Relapse occurred in 13 patients and no telomerase activity was detected in 3 recurrent tumours. CONCLUSION: Telomerase activity may be used as an objective parameter inversely related to tumour differentiation. Prognosis in telomerase-negative tumours is worse than that of the telomerase-positive group.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias de Cabeça e Pescoço/enzimologia , Telomerase/metabolismo , Idoso , Feminino , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fumar/genética , Fumar/metabolismo , Telômero/metabolismoRESUMO
BACKGROUND: Telomerase, a ribonucleoprotein complex catalysing synthesis of telomeric DNA, is an essential cellular immortalizing factor whose activation is a critical step in the progression to malignancy. An important agent maintaining the balance between proliferation, differentiation and apoptosis of intestinal epithelial cells in crypts is butyrate, which is formed in the gastrointestinal tract by anaerobic bacterial fermentation. It inhibits cell growth, induces differentiation and triggers apoptosis in neoplastic colonocytes. MATERIALS AND METHODS: In this study, the responses of adenocarcinoma (HT-29) and fetal (FHC) human colon cells to 5 mM sodium butyrate (NaBt) have been compared. RESULTS: Despite the similar general response of both cell lines to NaBt, i.e., G0/G1 arrest, decrease of growth rate and increase of differentiation (as indicated by alkaline phosphatase activity), they differ in the level and dynamics of the measured parameters. Telomerase activity and the level of mRNA for its catalytic subunit (hTERT) decline significantly after 48 hours, reaching a complete inhibition after 144 hours. While both cell lines show similar kinetics of hTERT transcriptional silencing, the down-regulation of telomerase activity is faster in FHC cells. Correspondingly, we show that a candidate posttranscriptional regulation step, differential splicing of hTERT mRNA, may be involved in the faster loss of telomerase activity in FHC cells. CONCLUSION: Differences in hTERT mRNA splicing may represent a useful marker of telomere metabolism in normal and malignant colon cells and that these changes may be connected with different cytokinetic patterns of these cells.