The tumor suppressor function of LOX in normal prostate

The tumor-suppressor function of 15-LOX-2 in normal prostate epithelial cells may be explained by the induction of replicative senescence [14,15]. Thus, 15-LOX-2 is overexpressed in age-dependent prostatic hyperplasia, but cell senescence may hinder progression to malignant transformation. Notwithstanding arachidonic acid, additional exogenous compounds found in foodstuffs may invoke 15-LOX-2 mediated growth arrest in PCa cells; for instance, docosahexaenoic FTI 277 HCl (DHA) has been shown to be metabolized by 15-LOX-2 to different 17-hydroxy DHA derivatives, which induce this effect via a PPARγ-dependent pathway [16]. Hence, the opposing roles of the 15-LOX isozymes in PCa are in wide agreement. The necessity for this duality is still under scrutiny.
Renal cell carcinoma Lipoxygenase involvement in renal cell carcinoma (RCC) development has been scarcely probed. There is one report on macrophages in the renal tumor microenvironment which show an upregulated expression of 15-LOX-2, but not 15-LOX-1, and enhanced production of 15-HETE. Pharmacologic inhibition of LOX promoted the production of CCL2 and IL-10 by these tumor-associated macrophages, suggesting 15-LOX-2 supports immune evasion by tumor cells [17]. Notably, tumor cells were obtained from newly diagnosed patients. On the other hand, a different report indicated enhanced expression of 15-LOX-1 in early RCC samples [18]. This expression was decreased in progressive tumor biopsies. The differences reported in 15-LOX-1 levels in RCC may stem from different methodologies: in the former study polymerase chain reaction (PCR) and Western blotting were used, whereas in the latter, immunohistochemistry was the method of choice. In sum, the scarcity of data regarding 15-LOX expression in RCC does not allow a definitive conclusion as to its role in this malignancy.
Lung cancer A lung carcinoma cell line was demonstrated by Brinckmann and Kuhn [19] to express an indeterminate 15-LOX after culturing with interleukin 4 (IL-4), a type 2 cytokine that exerts a similar effect on human monocytes/macrophages [20]. Detectable mRNA levels of both indeterminate 15-LOX in non-small lung carcinoma (NSCLC) cell lines were also reported by Moody et al. in the absence of IL-4 [21]. Along these lines, nordihydroguaiaretic acid (NDGA), a nonspecific LOX inhibitor, inhibited NSCLC cell growth and induced its apoptosis [21]. This effect, however, cannot be solely ascribed to either 5- or 15-LOX due to the nonspecific inhibition by NDGA. The expression of 15-LOX-2 in lung carcinoma biopsies was explored as well [22]. In benign lung tissue, 15-LOX-2 immunostaining was confined to type II pneumocytes (known to express PPARγ), especially in reactive areas. Among the various lung tumor types, 15-LOX-2 expression was detected only in NSCLC, and not in small cell carcinoma, which is more aggressive biologically. Tumor stage and patient survival, however, were not significantly correlated with 15-LOX-2 expression [22]. A murine model of Lewis lung carcinoma (LLC) was used by Harats et al. [23] to study the effect of endothelial 15-LOX-1 expression on lung cancer. Transgenic mice harboring endothelial cells overexpressing 15-LOX-1 under regulation of the preproendothelin-1 promoter were injected with LLC cells. Primary tumor and metastasis growth rates were diminished by 15-LOX-1 overexpression, as compared to control mice, with evident necrosis and apoptosis of tumor cells. 15-LOX-1 may act as a tumor suppressor in lung carcinoma through p53. After treatment with IL-4, A549 human lung carcinoma cells showed an increased expression of 15-LOX-1, with a concomitant rise in the expression of downstream targets of p53, a well-established tumor suppressor [24]. This is possibly achieved through binding of DNA-dependent protein kinase (DNA-PK), which was shown to precipitate with 15-LOX-1. Enhanced phosphorylation of p53 ensued, and this was reduced by knockdown of DNA-PK. The levels of the 15-LOX metabolites, 13-HODE and 15-HETE, were shown to be reduced in NSCLC biopsies [25]. In a murine model of a tobacco carcinogen-induced lung carcinoma, a drop in mRNA and protein levels of 12/15-LOX as well as the levels of 15-HETE were noted prior to the development of pronounced lung tumors. A similar decrease in PPARγ activity was found in this model, again preceding a significant rise in tumor numbers. The NSCLC cell line A549 also express upregulated levels of 15-LOX-1 and 15-LOX-2 mRNA after exposure to white tea extract (WTE) [26]. Apoptosis of NSCLC cells treated with WTE was demonstrated using enzyme-specific immunoassay (EIA), and was partially blocked by NDGA and the PPARγ inhibitor GW9662. The expression of 15-LOX-1 was found during terminal differentiation of human bronchial epithelial cells in air–liquid interface cultures, but was missing from lung cancer cell lines [27]. Along with more elaborate differentiation events missing in colonic cancer cell lines following 15-LOX-1 RNA knockdown, this suggested the involvement of 15-LOX-1 in differentiation processes abolished by malignant transformation.