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    • br Colorectal carcinoma The growth rate of murine

    2023-05-25


    Colorectal carcinoma The growth rate of murine colon adenocarcinoma tumors decreased upon inhibition of 5-LOX, an enzyme that harbors counteracting properties to 15-LOX [28]. It is not clear whether 15-LOX was associated with this phenomenon, but its expression is induced in the colon carcinoma cell line HTB 38 following treatment with IL-4 [19]. Expression of 15-LOX-1 in colorectal carcinoma tumor samples was found in high percentage and was more prominent than in adjacent normal tissue, using both Western blotting and immunohistochemistry as detection methods [29]. Conversely, Shureiqi et al. [30] reported a markedly reduced expression of 15-LOX-1 in both colorectal tumors and transformed colonic cell lines, detected by immunohistochemical staining along with diminished levels of 13-HODE, a major 15-LOX-1 metabolite. By Western blotting no difference in 15-LOX-1 expression was found. 13-HODE was also found to induce apoptosis in CRC cell lines [31], and its levels increased following treatment with apoptosis-inducing non-steroidal anti-inflammatory drugs (NSAID) [31]. Along these lines, pharmacologic inhibition of 15-LOX-1 blocked the effect of NSAIDs [31]. In the CRC cell line HCT-116, overexpression of 15-LOX-1 led to down-regulation of p21, a target of the tumor-suppressor gene p53, which was inhibited by NDGA and restored by 13-HODE [32]. This down-regulation was accompanied by increased cell growth, suggesting a pro-tumorigenic role for 15-LOX-1 metabolites. Of note, Zhu et al. countered this notion by demonstrating up-regulation of p53 and its targets following transfection of the same cell line with enzymatically inactive 15-LOX-1 [24]. Thus, 15-LOX might exert opposing actions pending on the presence of catalytic activity. Inhibition of cyclooxygenase-1 (COX-1) induces apoptosis in CRC artesunate synthesis in vitro with a concomitant rise in 15-LOX-1 expression [33]. This increased expression may depend on increased intracellular levels of cyclic guanylyl monophosphate (cGMP), with subsequent activation of protein kinase G (PKG) [33]. The decreased expression of 15-LOX-1 in CRC tissue may stem from transcriptional regulation of the GATA-6 transcription factor. Increased expression of GATA-6 mRNA was found in a CRC cell line, and a GATA binding site was demonstrated in the 15-LOX-1 promoter region in these cells [34]. When CRC tissue from biopsy samples was inspected, GATA-6 was over-expressed as compared to normal colonic tissue [35]. GATA-6 knockdown increased 15-LOX-1 expression and apoptosis in CRC cell lines treated with sodium butyrate (a histone deacetylase inhibitor) or NSAIDs [35]. Other mechanisms proposed by the same group for transcriptional silencing of 15-LOX-1 in CRC include the association of DNA methyltransferases (DNMTs) with the 15-LOX-1 promoter [36], and the nucleosome remodeling and histone deacetylase (NuRD) repression complex [37]. Adenoviral vector delivery was used to enhance 15-LOX-1 expression in various CRC cell lines, with subsequent restoration of gene expression and enzymatic activity [38]. CRC cell survival in vitro and growth of CRC xenografts in vivo were significantly inhibited, alongside down-regulation of anti-apoptotic proteins and induction of apoptosis [38]. These findings suggested for the first time that 15-LOX-1 might be used as a molecular target for cancer therapy. To establish the therapeutic potential of 15-LOX-1 in CRC, a mouse model with stable human transgene expression was created [39]. Intestinal epithelial targeting was achieved through the villin promoter, and was confirmed by RT-PCR and immunoblotting. Experimental tumorigenesis with azoxymethane was significantly suppressed in 15-LOX-1-transgenic mice in comparison with wild-type mice [39]. Moreover, the expression of tumor necrosis factor (TNF)-α and its target, inducible nitric oxide synthase (iNOS), were decreased in colonic cells, as was the activation of nuclear factor-kappa B (NF-κB) [39]. The reduction in the activity of NF-κB, a critical component in inflammation, was found to directly emanate from 15-LOX-1 overexpression, and thus underscores the important role of 15-LOX-1 in the resolution of inflammation [40]. Similarly, 15-LOX might be involved in the termination of pathologic processes that upon extension may lead to terminal cell de-differentiation and ultimately tumorigenesis [40]. The consistent findings on tumor suppression by 15-LOX-1 in CRC have led the Shureiqi group to conduct a clinical trial probing the association between the effect of celecoxib, a selective COX-2 inhibitor, on colorectal endothelial polyps, and the expression of 15-LOX-1 and GATA-6. This study is currently ongoing (NCT00503035, see references under National Cancer Institute).