Abstract 2893: p53 suppresses neuroendocrine carcinoma progression by inhibiting cell growth associated with mTOR pathway activation

Abstract

Abstract p53 suppression of AKT/mTOR pathway signaling was recently identified as a novel mechanism to negatively regulate cell growth. Despite the well-established down-regulation of AKT/mTOR signaling by p53 mediated gene transcription in cells, the contribution of this novel p53 function to tumor suppression in vivo remains unclear. PI3K-AKT pathway activation plays a central role in neuroendocrine carcinomas such as medullary thyroid cancer (MTC): however, little is known about the molecules that influence this pathway to regulate tumor growth. Studies in human tumors and murine models suggest that the Rb and p53 have critical and cooperative functions that suppress carcinogenesis, especially in the context of cancers with a neuroendocrine phenotype such as MTC and small cell lung cancer. The objective of this study was to test the hypothesis that p53 cooperates with Rb to suppress neuroendocrine carcinogenesis by suppressing mTOR pathway signaling. A conditional mouse model was generated using Cre-lox technology and tetracycline regulated gene ablation wherein MTC is initiated by Rb inactivation. Additional conditional loss of p53 in this model resulted in a dramatic increase in MTC progression leading to lethality at a median age of 4 months versus >9 months for mice with Rb ablation alone. Combined p53/Rb deficient tumors were significantly larger than Rb deficient tumors in 4 month old animals (10.20 ± 0.36 mm (n=15) vs. 2.00 ± 0.00 mm (n=5); p<0.0001). In addition, p53 loss resulted in increased phosphorylated histone H3 positive tumor cells by immunohistochemical analysis and decreased TUNEL positive tumor cells, thereby identifying enhanced cellular proliferation and survival as underlying mechanisms promoting tumor progression after p53 loss. mTOR signaling was significantly up-regulated in Rb/p53 deficient tumors as compared to Rb deficient tumors as demonstrated by increased phosphorylated S6 kinase expression by western blot analysis. mTOR pathway activation occurred independent of a concurrent increase in AKT or MAPK activation as assessed by phosphorylation of AKT or MEK, respectively. Together, these results demonstrate that p53 inhibits progression of Rb initiated neuroendocrine carcinoma by suppressing cellular proliferation and survival. Moreover, these data provide evidence that p53 negatively regulates mTOR signaling, a key factor that promotes cell growth, in the context of tumorigenesis in vivo thereby implicating mTOR pathway suppression as a critical p53 tumor suppressive function. These studies establish a link between the genetic traits of the tumor and signaling pathway activation that has important implications for designing therapies to combat these currently treatment resistant malignancies. 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 2893. doi:10.1158/1538-7445.AM2011-2893