Global expression changes of LNCaP and PC3 cells in response to acute Notch activation

Adenocarcinomas of the prostate arise as multifocal heterogeneous lesions as the likely result of genetic and epigenetic alterations and deranged cell-cell communication. Notch signaling is an important form of intercellular communication with a role in growth/differentiation control and tumorigenesis. Contrasting reports exist in the literature on the role of this pathway in prostate cancer (PCa) development. We report here that Notch1 expression is significantly reduced in a substantial fraction of human PCas, while it is unaffected or even increased in others. Global analysis of gene expression shows that increased Notch1 expression in PCa cells or samples, while counteracting to a significant extent the abnormal program of gene expression that is characteristically altered in clinically occurring tumors, enhances some other aberrant aspects of this program. In particular, down-modulation of Notch1 expression and activity in immortalized normal prostate epithelial cells increases their proliferation potential, while increased Notch1 activity in PCa cells suppresses growth and tumorigenicity. While control of p21Cip1/WAF1 expression by increased Notch1 activity through a Smad3-dependent mechanism can explain the growth inhibitory effects, pro-oncogenic genes, like EPAS1 and CXCL6, are concomitantly up-regulated by Notch in PCa cell lines resistant to Notch1 growth inhibition, in agreement with enhanced tumorigenic behavior.

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