Abstract 1061: Context dependent tumor suppressor activity of the ERK pathway explains its inverse correlation with malignancy in prostate neoplasms

Abstract This study gives considerable insight about the antagonistic functions associated to the ERK1/2 kinases activation during tumorigenesis. The Ras proteins are small GTPases known for their role in growth factor signals transmission from membrane receptors. Oncogenic forms of Ras are found in approximately 25% of all human cancers and are generally associated with uncontrolled cell proliferation. However, expression of oncogenic Ras in normal cells is associated with accumulation of DNA damage, activation of tumor suppressors p53 and Rb and cellular senescence. It is known that Ras activates multiple signaling pathways, such as the PI3K/Akt pathway, the Ral pathway and the classical Raf/Mek/Erk MAP Kinase pathway. Our study demonstrates that Erk1/2 (Extracellular-Regulated Kinases) are crucial for H-RasV12-induced senescence in normal human fibroblasts. We have shown that the expression of different small hairpin RNAs against Erk1 or Erk2 in normal human fibroblasts causes an important bypass of H-RasV12-induced senescence and the acquisition of several characteristics of transformed cells. This finding strongly suggests that the Raf/Mek/Erk pathway can be anti-oncogenic in some contexts by activating the tumor suppressor pathways regulating senescence. We propose a model where a moderated level of activated Erk promotes proliferation and potentially transformation, but a higher level of activated Erk, over a given threshold, activates senescence. Consistent with our model, expression studies in benign prostatic hyperplasia (BPH), a benign tumor of the prostate, reveal that BPH cells display high level of senescence markers and activated Erk in comparison with normal cells and many tumor samples. Similarly, we observed a negative correlation between the p-Erk1/2 levels in the nuclei of cancer cells from different prostate tumors and the Gleason score or the biochemical relapse after chemotherapy. Such correlations suggest that cells with lower p-Erk1/2 levels are in general from more aggressive prostate cancers. To explain the phenotype of transformed cells that bypass senescence in our experiments, an analysis of signaling pathways known to contribute to transformation by Ras was performed. We observed that the Raf/Mek/Erk pathway exerts a negative control on the PI3K/Akt pathway, itself activated by Ras. Thus, cells that bypass H-RasV12-induced senescence by decreasing Raf/Mek/Erk activity show a strong hyperactivation of Akt, which could explain their anarchic proliferation. Our results suggest caution in the clinical use of inhibitors of the ERK pathway alone but also the possibility of designing novel antitumor agents that increase the ERK activity over the threshold required to induce cellular senescence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1061. doi:10.1158/1538-7445.AM2011-1061

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