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 2α (eIF2α) induces the repression of cyclin D1 translation. Moreover, the PERK-eIF2α-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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 4 / genetics
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Activating Transcription Factor 4 / metabolism
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Adenomatous Polyposis Coli Protein / physiology*
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Blotting, Western
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Cell Transformation, Neoplastic / drug effects*
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Colonic Polyps / drug therapy*
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Colonic Polyps / metabolism
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Colonic Polyps / pathology
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Endoplasmic Reticulum Stress / drug effects*
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Humans
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Immunoprecipitation
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Tumor Cells, Cultured
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Unfolded Protein Response / drug effects
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eIF-2 Kinase / genetics
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eIF-2 Kinase / metabolism
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ortho-Aminobenzoates / pharmacology*
Substances
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Adenomatous Polyposis Coli Protein
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Anti-Inflammatory Agents, Non-Steroidal
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Atf4 protein, mouse
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RNA, Messenger
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ortho-Aminobenzoates
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Cyclin D1
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Activating Transcription Factor 4
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tolfenamic acid
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PERK kinase
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Protein Serine-Threonine Kinases
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eIF-2 Kinase
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eIF2alpha kinase, mouse