Tumor-suppressing 15-Lipoxygenase-2

Abstract

Lipoxygenases (LOX) comprise a family of non-heme-iron-containing proteins that catalyze the dioxygenation of polyunsaturated fatty acids to form bioactive lipids. Metabolism of arachidonic acid by LOXs leads to the formation of regioisomeric cis/trans-conjugated hydroxyeicosatetraenoic acids (HETEs), leukotrienes, lipoxins, and hepoxilins. Dependent on the predominant position of the incorporation of hydroperoxy group, LOXs are classified as 3-, 5-, 8-, 12(S)-, 12(R)-, and 15-LOXs, whose main products are 3(S)-, 5(S)-, 8(S)-, 12(S), 12(R)-, and 15(S)-HETE, respectively. There are two 15-LOX: 15-LOX1 (gene: ALOX15) and 15-LOX2 (gene: ALOX15B). 15-LOX1, whose murine ortholog is leukocyte-type 12-LOX, prefers linoleic acid as the substrate to form 13(S)-HODE, although it can convert arachidonic acid to 15(S)-HETE and, to a lesser extent, 12(S)-HETE. On the other hand, 15-LOX2 mainly uses arachidonic acid to form 15(S)-HETE.1 The involvement of LOXs in carcinogenesis is complex, since both tumor-promoting and -suppressing activities are reported for the various members of LOX family. A number of studies suggest 15-LOX2 as a functional tumor suppressor, particularly in the prostate. Its expression or activity is frequently suppressed during carcinogenesis of prostate, lung, esophageal, and sebaceous gland. Restoration of 15-LOX2 expression in prostate cancer cells inhibited DNA replication, caused G0/G1 arrest, reduced tumor growth and even tumor development.2,3 Interestingly, when 15-LOX2 is expressed in mouse prostate, the transgenic mice presented indications of prostate hyperplasia,4 suggesting the complex function of 15-LOX2 in disrupting tissue homeostasis in the mouse prostate. Suraneni et al.5 in this issue presented experimental evidence unequivocally establishing the tumor-suppressing activities of 15-LOX2. By crossing 15-LOX2 transgenic mice with a Hi-Myc mouse model for prostate cancer, they found that the presence of 15-LOX2 inhibited Myc-induced tumor development in the prostate of double transgenic mice. Given the frequent amplification of Myc in human prostate cancer, it is reasonable to extrapolate that the loss of 15-LOX2 can contribute to Myc-induced prostate carcinogenesis. However, whether Myc suppresses 15-LOX2 expression remains to be elucidated. A common biological effect of 15-LOX2 is cell senescence. Suraneni et al. observed an increased cell senescence in the mouse prostate with expression of human 15-LOX2, possibly through induction of RB1CC1 expression.4 In this issue, Suraneni extended this observation.5 They found an upregulation of RB1CC1 in the prostates of double transgenic Myc;LOX mice when compared with the Hi-Myc prostates. Paradoxically, RB1CC1 is found upregulated, instead of being suppressed as 15-LOX2, in human prostate cancers, suggesting that the link between 15-LOX2 and RB1CC1 can be compounded by many other extraneous factors uniquely present in the human prostate. An important question is how to harness the tumor-suppressive activities of 15-LOX2 as possible prevention and treatment of prostate cancer. Reactivation of 15-LOX2 expression in human prostate cancer cells, while conceptually plausible, requires detailed understanding how 15-LOX2 is suppressed during carcinogenesis and identification of druggable targets. Another approach is to utilize the arachidonate product of 15-LOX2, 15(S)-HETE, to suppress prostate cancer. A limitation for this approach is the uncertainty whether 15(S)-HETE can recapitulate the tumor-suppressive activities of 15-LOX2. 15(S)-HETE treatment has been shown to suppress prostate cancer cell growth and induce RB1CC1, as 15-LOX2 did.3,5 However, the enzymatic activity of 15-LOX2 seems dispensable for its tumor-suppressing activities. PC-3 cells transfected with a splice variant of 15-LOX2, 15-LOX2sv-b, which did not have the capacity of synthesizing 15(S)-HETE, also had reduced tumor development.3 This evidence suggests that 15(S)-HETE may not fully recapitulate the tumor-suppressing activities of 15-LOX2. Further studies are needed to resolve the complex roles of lipoxygenases in cancers. From a gene evolution perspective, all ALOX genes come from one ancestral gene that has duplicated several times (Fig. 1). Comparisons of the orthologous genes between mouse and human ALOX5 or ALOX12R demonstrate that those genes have more than 85% amino acid identities. On the other hand, comparisons of paraologous ALOX genes, such as ALOX15 vs ALOX15B or ALOX12 vs ALOX15B, reveal only 40% amino acids identities. However, the amino acid identity between human ALOX15B and mouse ALOX8 is as high as 78%. In this sense, the murine ALOX8 is the ortholog of human ALOX15B, although their metabolic products can be different. Studies show that 8-LOX possesses anti-proliferation and anti-tumorigenic activities, as does 15-LOX2.6,7 Although 8-LOX expression is not detected in the prostate of 3- or 6-mo-old mice (human equivalent ages of 8 or 16 y), it is unknown whether 8-LOX is expressed in more senescent or diseased mouse prostate. Given the remarkably similar organization of murine ALOX8 and human ALOX15B in their respective genome (Fig. 1), further studies are needed to determine whether deletion of ALOX8 can lead to increased carcinogenesis, particularly in the prostate. Figure 1. Evolution of ALOX genes. Based on the arrangements and sequence homology, it is deduced all ALOX genes are derived from one ancient ALOX gene through duplications and evolutions. Note the remarkable similarity in genomic localization ...