Abstract 784: Chronic stress promotes tumorigenesis through attenuation of p53 function .

Abstract

Abstract Tumor suppressor p53 plays a crucial role in preventing tumor formation. p53 responds to stress signals and transcriptionally regulates its target genes to start various cellular responses, thus preventing tumor initiation and/or progression. p53 is the most frequently-mutated gene in tumors; approximately 50% of human tumors harbor inactivating mutations in p53. The p53 protein is under tight regulation in cells. Loss or the attenuation of p53 function affects cancer risk and tumor progression. Epidemiological studies strongly suggest that chronic psychological stress has negative influences on the onset, progression and mortality of cancers. Studies employing chronic restraint or social isolation in mice, two well-established chronic stress models, have shown that chronic stress enhances tumor growth and metastasis in xenograft tumor assays. However, the direct evidence that chronic stress promotes tumorigenesis in vivo is still lacking, and furthermore, the molecular mechanisms by which chronic stress promotes tumorigenesis remain unclear. To investigate the impact of chronic stress upon tumorigenesis in vivo, we established a mouse model that combines chronic restraint and ionizing radiation (IR)-induced tumorigenesis. IR induces tumorigenesis in both mice and humans. p53+/- mice are susceptible to IR-induced tumorigenesis; a single dose of 4 Gy IR results in the development of tumors, mainly lymphomas, in p53+/- mice. By employing this mouse model system, we found that in p53+/- C57BL6/J mice, chronic restraint stress greatly promoted IR-induced tumorigenesis; chronic restraint reduced IR-induced tumor latency from ∼49 weeks to ∼38 weeks of median survival age (p=0.004). This result provides direct evidence that chronic stress enhances tumorigenesis in vivo. Furthermore, chronic restraint decreased p53 protein levels and function in mice, and promoted the growth of human xenograft tumors in a largely p53-dependent manner. Chronic restraint greatly promotes the growth rate of HCT116 p53+/+ tumors (increased by 3.77-fold) in mice; and has significantly less pronounced promoting effect on the growth of HCT116 p53-/- tumors (increased by 1.52-fold) (p<0.0001). It is known that chronic stress increases the levels of glucocorticoids, which mediate many of the effects of chronic stress. Interestingly, we found that glucocorticoids elevated during chronic restraint mediate the inhibitory effect of chronic restraint on p53. We further identified that the induction of serum- and glucocorticoid-induced protein kinase (SGK1), a transcriptional target gene of glucocorticoids/glucocorticoids receptor, leads to the increase of MDM2 activity and the decrease of p53 function. Taken together, our study demonstrates that chronic stress promotes tumorigenesis in mice, and the attenuation of p53 function though glucocortcoids/SGK1/MDM2 is an important underlying mechanism. Citation Format: Cen Zhang, Meihua Lin, Yuhan Zhao, Tongsen Zheng, Jiabei Wang, Arnold Levine, Zhaohui Feng, Wenwei Hu. Chronic stress promotes tumorigenesis through attenuation of p53 function . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 784. doi:10.1158/1538-7445.AM2013-784