Tumor-suppressing 15-Lipoxygenase-2

Lipoxygenases (LOX) comprise a family of non-heme-iron-containing proteins that cata-lyze 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), leukot-rienes, 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-LOwXs, 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 G 0 /G 1 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 pros-tate 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 carcino-genesis. 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 pros-tate 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 pros-tates. Paradoxically, RB1CC1 is found upregu-lated, instead of being suppressed as 15-LOX2, in human prostate cancers, suggesting that the …