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The involvement of endoplasmic reticulum stress in the suppression of colorectal tumorigenesis by tolfenamic acid.


ABSTRACT: The nonsteroidal anti-inflammatory drug tolfenamic acid has been shown to suppress cancer cell growth and tumorigenesis in different cancer models. However, the underlying mechanism by which tolfenamic acid exerts its antitumorigenic effect remains unclear. Previous data from our group and others indicate that tolfenamic acid alters expression of apoptosis- and cell-cycle arrest-related genes in colorectal cancer cells. Here, we show that tolfenamic acid markedly reduced the number of polyps and tumor load in APC(min)(/+) mice, accompanied with cyclin D1 downregulation in vitro and in vivo. Mechanistically, tolfenamic acid promotes endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) signaling pathway, of which PERK-mediated phosphorylation of eukaryotic translation initiation factor 2? (eIF2?) induces the repression of cyclin D1 translation. Moreover, the PERK-eIF2?-ATF4 branch of the UPR pathway plays a role in tolfenamic acid-induced apoptosis in colorectal cancer cells, as silencing ATF4 attenuates tolfenamic acid-induced apoptosis. Taken together, these results suggest ER stress is involved in tolfenamic acid-induced inhibition of colorectal cancer cell growth, which could contribute to antitumorigenesis in a mouse model.

SUBMITTER: Zhang X 

PROVIDER: S-EPMC3855893 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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The involvement of endoplasmic reticulum stress in the suppression of colorectal tumorigenesis by tolfenamic acid.

Zhang Xiaobo X   Lee Seong-Ho SH   Min Kyung-Won KW   McEntee Michael F MF   Jeong Jin Boo JB   Li Qingwang Q   Baek Seung Joon SJ  

Cancer prevention research (Philadelphia, Pa.) 20131008 12


The nonsteroidal anti-inflammatory drug tolfenamic acid has been shown to suppress cancer cell growth and tumorigenesis in different cancer models. However, the underlying mechanism by which tolfenamic acid exerts its antitumorigenic effect remains unclear. Previous data from our group and others indicate that tolfenamic acid alters expression of apoptosis- and cell-cycle arrest-related genes in colorectal cancer cells. Here, we show that tolfenamic acid markedly reduced the number of polyps and  ...[more]

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