Department of Radiation Oncology and Department of Pediatrics, Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA.
Proc Natl Acad Sci U S A. 2012 May 1;109(18):7013-8. doi: 10.1073/pnas.1203930109. Epub 2012 Apr 16.
Epidemiological studies strongly suggest that chronic psychological stress promotes tumorigenesis. However, its direct link in vivo and the underlying mechanisms that cause this remain unclear. This study provides direct evidence that chronic stress promotes tumorigenesis in vivo; chronic restraint, a well-established mouse model to induce chronic stress, greatly promotes ionizing radiation (IR)-induced tumorigenesis in p53(+/-) mice. The tumor suppressor protein p53 plays a central role in tumor prevention. Loss or attenuation of p53 function contriubutes greatly to tumorigenesis. We found that chronic restraint decreases the levels and function of p53 in mice, and furthermore, promotes the growth of human xenograft tumors in a largely p53-dependent manner. Our results show that glucocorticoids elevated during chronic restraint mediate the effect of chronic restraint on p53 through the induction of serum- and glucocorticoid-induced protein kinase (SGK1), which in turn increases MDM2 activity and decreases p53 function. Taken together, this study demonstrates that chronic stress promotes tumorigenesis in mice, and the attenuation of p53 function is an important part of the underlying mechanism, which can be mediated by glucocortcoids elevated during chronic restraint.
流行病学研究强烈表明，慢性心理压力会促进肿瘤发生。然而，其在体内的直接联系和导致这种情况的潜在机制尚不清楚。本研究提供了直接证据，表明慢性应激会促进体内肿瘤发生；慢性束缚，一种已建立的诱导慢性应激的小鼠模型，极大地促进了 p53(+/-) 小鼠的电离辐射（IR）诱导肿瘤发生。肿瘤抑制蛋白 p53 在肿瘤预防中发挥核心作用。p53 功能的缺失或减弱极大地促成了肿瘤发生。我们发现慢性束缚会降低小鼠中 p53 的水平和功能，并且以很大程度上依赖于 p53 的方式促进人异种移植肿瘤的生长。我们的结果表明，慢性束缚期间升高的糖皮质激素通过诱导血清和糖皮质激素诱导蛋白激酶（SGK1）介导慢性束缚对 p53 的影响，进而增加 MDM2 活性并降低 p53 功能。总之，这项研究表明，慢性应激会促进小鼠的肿瘤发生，而 p53 功能的减弱是潜在机制的重要组成部分，这可以通过慢性应激期间升高的糖皮质激素介导。
