15-Lipoxygenase-1 mediates nonsteroidal anti-inflammatory drug-induced apoptosis independently of cyclooxygenase-2 in colon cancer cells

We previously found (I. Shureiqi et al., Carcinogenesis (Lond.), 20: 1985-1 995, 1999; I. Shureiqi et al., J. Natl. Cancer Inst., 92: 1136-1142, 2000) that (a) 15-lipoxygenase-1 (15-LOX-1) protein and its product 13-S- hydroxy octadecadienoic acid (13-S-HODE) are decreased; and (b) nonsteroidal anti-i nflammatory drug (NSAID)-induced 15-LOX-1 expression is critical to NSAID-i nduced apoptosis in colorectal cancer cells expressing cyclooxygenase-2 (CO X-2). We used the NSAIDs sulindac sulfone (COX-2-independent) and NS-398 (a COX-2 inhibitor) to assess NSAID upregulation of 15-LOX-1 in relation to C OX-2 inhibition during NSAID-induced apoptosis in the DLD-1 (COX-2-negative ) colon cancer cell line. We found thats (a) NSAIDs up-regulated 15-LOX-1, which preceded apoptosis; and (b) 15-LOX-1 inhibition blocked NSAID-induced apoptosis, which was restored by 13-S-HODE but not by its parent, linoleic acid. NSAIDs can induce apoptosis in colon cancer cells via up-regulation of 15-LOX-1 in the absence of COX-2.