Colorectal carcinoma (CRC) is often lethal when invasion and ⁄ or metastasis occur. 15-Lipoxygenase-1 (15-LO-1), a member of the inflammatory eicosanoid pathway, oxidatively metabolizes linoleic acid and its expression is repressed in CRC. In this study, we investigated the hypothesis that the lack of 15-LO-1 expression in CRC cells might contribute to tumorigenesis. Therefore we introduced 15-LO-1 into HCT-116 and HT-29 cells that do not have detectable levels of 15-LO-1. Our data indicate that expression of 15-LO-1 significantly decreased cell proliferation and increased apoptosis. In addition, we observed a reduction in adhesion to fibronectin, anchorage-independent growth on soft agar, cellular motility and ability to heal a scratch wound, and migratory and invasive capacity across Matrigel. 15-LO-1 expression also reduced the expression of metastasis associated protein-1, a part of the nucleosome remodeling and histone deacetylase silencing complex. We propose that 15-LO-1 expression in CRC might contribute to the inhibition of metastatic capacity in vitro and can be exploited for therapeutic purposes. (Cancer Sci 2009; 100: 2283-2291 C olorectal cancer is one of the leading causes of cancerrelated deaths throughout the world.(1) There is growing evidence that supports a functional role for the inflammatory COX and LO enzymes in cancer development.(2-4) LOs, which can oxygenate arachidonic acid and linoleic acid, can be classified as procarcinogenic or anticarcinogenic; thus, 5-, 8-, and 12-LO are classified as procarcinogenic, whereas 15-LO-2 is anticarcinogenic.(5,6) 15-LO-1, however, has a controversial role in cancer. This enzyme preferentially catalyzes the conversion of linoleic acid to 13(S)-HODE. (7,8) 15-LO-1 has been unambiguously shown to have a protumorigenic role in prostate cancer and preliminary reports in CRC also assigned a procarcinogenic role to 15-LO-1 through activation of the MAPK pathway. (9)(10)(11)(12)(13)(14)(15) However, surprisingly, subsequent studies have indicated a tumor suppressive nature of the enzyme as its expression was shown to be lost in CRC by immunohistochemistry. (16,17) Promoter analysis of ALOX15 indicated that expression of the gene is suppressed in tumors by several mechanisms acting in concert, such as promoter methylation, (18) binding of the nucleosome remodeling and histone deacetylase repression complex, (19) and through the overexpression of the transcription factor GATA-6. (20) Forced expression of the enzyme in various colon cancer cell lines has shown a downregulation of anti-apoptotic proteins and activation of apoptotic pathways. (21)(22)(23)(24)(25) The gene can also be transcriptionally reactivated by histone deacetylase inhibitors and non-steroidal anti-inflammatory drugs to induce apoptosis. (26,27) Additionally, selective molecular targeting of 15-LO-1 expression was shown to be sufficient to inhibit tumorigenesis in mice.(24) A similar tumor suppressive role of 15-LO-1 has also been observed in bladder and pancreatic cancers. (11,28) Although mu...

CLX (celecoxib), a selective COX-2 (cyclo-oxygenase-2) inhibitor, has numerous pleiotropic effects on the body that may be independent of its COX-2 inhibitory activity. The cancer chemopreventive ability of CLX, particularly in CRC (colorectal cancer), has been shown in epidemiological studies. Here we have, for the first time, examined the biophysical effects of CLX on the cellular membranes of COX-2 expressing (HT29) and COX-2 non-expressing (SW620) cell lines using ATR-FTIR (attenuated total reflectance-Fourier transform IR) spectroscopy and SL-ESR (spin label-ESR) spectroscopy. Our results show that CLX treatment decreased lipid fluidity in the cancer cell lines irrespective of COX-2 expression status. As metastatic cells have higher membrane fluidity, we examined the effect of CLX on the metastatic potential of these cells. The CLX treatment efficiently decreased the proliferation, anchorage-independent growth, ability to close a scratch wound and migration and invasion of the CRC cell lines through Matrigel. We propose that one of the ways by which CLX exerts its anti-tumorigenic effects is via alterations in cellular membrane fluidity which has a notable impact on the cells' metastatic potential.