The nonsteroidal anti-inflammatory drug tolfenamic acid (TA) has been shown to suppress cancer cell growth and tumorigenesis in different cancer models. However, the underlying mechanism by which TA exerts its anti-tumorigenic effect remains unclear. Previous data from our group and others indicate that TA alters expression of apoptosis- and cell cycle arrest-related genes in colorectal cancer cells. Here, we show that TA markedly reduced the number of polyps and tumor load in APCmin/+ mice, accompanied with cyclin D1 down-regulation in vitro and in vivo. Mechanistically, TA promotes endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) signaling pathway, of which PER... More
The nonsteroidal anti-inflammatory drug tolfenamic acid (TA) has been shown to suppress cancer cell growth and tumorigenesis in different cancer models. However, the underlying mechanism by which TA exerts its anti-tumorigenic effect remains unclear. Previous data from our group and others indicate that TA alters expression of apoptosis- and cell cycle arrest-related genes in colorectal cancer cells. Here, we show that TA markedly reduced the number of polyps and tumor load in APCmin/+ mice, accompanied with cyclin D1 down-regulation in vitro and in vivo. Mechanistically, TA 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 TA-induced apoptosis in colorectal cancer cells, as silencing ATF4 attenuates TA-induced apoptosis. Taken together, these results suggest ER stress is involved in TA-induced inhibition of colorectal cancer cell growth, which could contribute to anti-tumorigenesis in a mouse model.
