Metastasis is the major cause of cancer mortality. We therefore wanted to study the possible genetic changes acquired by these cancer cells in order to be endowed with metastatic capabilities. Several studies have identified genes which are differentially expressed in primary and secondary tumor growths. 15-lipoxygenase (ALOX15B) is one such gene. It encodes for an enzyme that takes part in arachidonic acid metabolism and has been characterized as a functional tumor suppressor in prostate cancer. The expression and activity of ALOX15B is frequently suppressed during the carcinogenic progress in the prostate, lungs, esophagus and sebaceous glands. However the exact role of ALOX15B as a tumor suppressor or the underlying mechanism behind its suppression in metastatic cancer cells remains largely unknown. Our initial in silico analyses from clinical samples showed that ALOX15B expression is attenuated in metastatic prostate cancer, compared to normal tissue or primary prostate cancer. Gene array studies across several cancer cell lines showed that ALOX15B expression is inversely correlated with invasiveness of the cell type. Gene clustering showed that ALOX15B is grouped with genes associated with an epithelial phenotype. ALOX15B expression was knocked down in immortalized non-transformed prostate as well as non/low invasive prostate cancer cell line. This had no effect on the proliferative indices in these cells, neither were the cells more resistant to apoptosis under normal growth conditions. However the cells were endowed with increased resistance to hypoxic stress. This was at least in part achieved by increased production of VEGF-A. Analyses of several pro-survival pathways identified that Akt signaling was hyper activated in these ALOX15B knocked down cells. This in turn led to a decreased FoxO transcriptional activity. Conversely, restoration of ALOX15B in low/non metastatic as well as highly metastatic prostate cancer cell lines decreased their basal level of Akt signaling along with increased FoxO activity and a concomitant decrease in VEGF-A production. Further experiments showed that ALOX15B regulates Akt activity by modulating its phosphorylation status. Luciferase tagged rat prostate cancer cells were engineered to over-express ALOX15B. Implantation of such cells in mice showed that cells with restored expression of ALOX15B showed no difference in growth kinetics of primary tumor growth, but a decrease in luciferase activity in the liver of such mice. To summarize, our data shows that loss of ALOX15B expression in prostate cancer cells endows such cells with pro-survival benefits which allows them to establish successful macro-metastases.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3424. doi:1538-7445.AM2012-3424

©2012 American Association for Cancer Research
2012