Chronic restraint stress attenuates p53 function and promotes tumorigenesis

Abstract

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.

Long-term study of subclinical Cushing^|^rsquo;s syndrome shows high prevalence of extra-adrenal malignancy in patients with functioning bilateral adrenal tumors

“…Moreover, mutations of tumor suppressor genes such as p53, MEN1 and ARMC5 have been observed in adrenocortical adenoma or hyperplasia [24,33,34]. Interestingly, glucocorticoids are reported to decrease p53 protein levels in mice and may promote tumorigenesis [35]. Some genes mutated in adrenal lesions are also altered in cancers derived from other organs.…”

Behavioral stress accelerates prostate cancer development in mice

“…In addition, the limited mechanistic information on signaling by stress hormones in various tumor cells makes it difficult to design new epidemiological studies and to interpret the results of previous ones that have addressed the role of stress in cancer progression and the therapeutic potential of beta blockers as an adjuvant anticancer therapy. Together with recent reports on stress-induced VEGF and IL-8 secretion (16,55), activation of FAK (56), and downregulation of p53 (57,58) that stimulate tumor angiogenesis, migration, invasion, and survival (26), our data highlight the connection between activation of the ADRB2/PKA axis and tumor-promoting effects of stress and introduce BAD phosphorylation as a target of stress or adrenaline signaling. Future experiments will determine whether stress activates the adrenaline/ADRB2/PKA/BAD pathway in prostate tumors and other human cancers.…”

The Regulation of Multiple p53 Stress Responses is Mediated through MDM2

“…89,90 SGK1 is a ubiquitously expressed serine-threonine kinase, which shares high sequence homology with AKT (~50% through their catalytic domain) and a similar consensus phosphorylation site RXRXXS/T with AKT. 91 Interestingly, similar to AKT, SGK1 activates MDM2 through phosphorylation of MDM2 at Ser-166/186, 87,92 which in turn down-regulates p53 function (Fig. 7).…”

“…87 This effect is largely mediated by serum-and glucocorticoidinduced protein kinase (SGK1), a gene regulated by glucocorticoids. Glucocorticoids bind to a glucocorticoid receptor, which then translocates to the nucleus and acts as a transcriptional factor to regulate the expression of its target genes, including SGK1.…”

“…Interestingly, recent studies suggest that neurohormones elevated during chronic stress down-regulate p53 through the activation of MDM2, which could be an important mechanism by which chronic stress promotes tumorigenesis. 87,88 Glucocorticoid hormones, Figure 6. The regulation of MDM2 by ribosomal stress.…”