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PLoS One. 2013 Apr 9;8(4):e61435. doi: 10.1371/journal.pone.0061435. Print 2013.

Effect of chronic restraint stress on human colorectal carcinoma growth in mice.

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Department of Biochemistry and Molecular Cell Biology, Institute of Medical Science, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.


Stress alters immunological and neuroendocrinological functions. An increasing number of studies indicate that chronic stress can accelerate tumor growth, but its role in colorectal carcinoma (CRC) progression is not well understood. The aim of this study is to investigate the effects of chronic restraint stress (CRS) on CRC cell growth in nude mice and the possible underlying mechanisms. In this study, we showed that CRS increased the levels of plasma catecholamines including epinephrine (E) and norepinephrine (NE), and stimulated the growth of CRC cell-derived tumors in vivo. Treatment with the adrenoceptor (AR) antagonists phentolamine (PHE, α-AR antagonist) and propranolol (PRO, β-AR antagonist) significantly inhibited the CRS-enhanced CRC cell growth in nude mice. In addition, the stress hormones E and NE remarkably enhanced CRC cell proliferation and viability in culture, as well as tumor growth in vivo. These effects were antagonized by the AR antagonists PHE and PRO, indicating that the stress hormone-induced CRC cell proliferation is AR dependent. We also observed that the β-AR antagonists atenolol (ATE, β1- AR antagonist) and ICI 118,551 (ICI, β2- AR antagonist) inhibited tumor cell proliferation and decreased the stress hormone-induced phosphorylation of extracellular signal-regulated kinases-1/2 (ERK1/2) in vitro and in vivo. The ERK1/2 inhibitor U0126 also blocked the function of the stress hormone, suggesting the involvement of ERK1/2 in the tumor-promoting effect of CRS. We conclude that CRS promotes CRC xenograft tumor growth in nude mice by stimulating CRC cell proliferation through the AR signaling-dependent activation of ERK1/2.

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