Lipoxygenase inhibitors abolish proliferation of human pancreatic cancer cells

Epidemiologic and animal studies have linked pancreatic cancer growth with fat intake, especially unsaturated fats. Arachidonic acid release from memb rane phospholipids is essential for tumor cell proliferation. Lipoxygenases (LOX) constitute one pathway for arachidonate metabolism, but their role i n pancreatic cancer growth is unknown. The expression of 5-LOX and 12-LOX a s well as their effects on cell. proliferation was investigated in four hum an pancreatic cancer cell lines (PANC-1, MiaPaca2, Capan2, and ASPC-1). Exp ression of 5-LOX and 12-LOX mRNA was measured by nested RT-PCR. Effects of LOX inhibitors and specific LOX antisense oligonucleotides on pancreatic ca ncer cell proliferation were measured by H-3-thymidine incorporation. Our r esults showed that (1) 5-LOX and 12-LOX were expressed in all pancreatic ca ncer cell lines tested, while they were not detectable in normal human panc reatic ductal cells; (2) both LOX inhibitors and LOX antisense markedly inh ibited cell proliferation in a concentration-dependent and time-dependent m anner; (3) the 5-LOX and 12-LOX metabolites 5-HETE and 12-HETE as well as a rachidonic and linoleic acids directly stimulated pancreatic cancer cell pr oliferation; (4) LOX inhibitor-induced growth inhibition was reversed by 5- HETE and 12-HETE. The current studies indicate that both 5-LOX and 12-LOX e xpression is upregulated in human pancreatic cancer cells and LOX plays a c ritical role in pancreatic cancer cell proliferation. LOX inhibitors may be valuable for the treatment of pancreatic cancer. (C) 1999 Academic Press.