LTB4 stimulates growth of human pancreatic cancer cells via MAPK and PI-3 kinase pathways

https://doi.org/10.1016/j.bbrc.2005.07.166Get rights and content

Abstract

We have previously shown the importance of LTB4 in human pancreatic cancer. LTB4 receptor antagonists block growth and induce apoptosis in pancreatic cancer cells both in vitro and in vivo. Therefore, we investigated the effect of LTB4 on proliferation of human pancreatic cancer cells and the mechanisms involved. LTB4 stimulated DNA synthesis and proliferation of both PANC-1 and AsPC-1 human pancreatic cancer cells, as measured by thymidine incorporation and cell number. LTB4 stimulated rapid and transient activation of MEK and ERK1/2 kinases. The MEK inhibitors, PD98059 and U0126, blocked LTB4-stimulated ERK1/2 activation and cell proliferation. LTB4 also stimulated phosphorylation of p38 MAPK; however, the p38 MAPK inhibitor, SB203580, failed to block LTB4-stimulated growth. The activity of JNK/SAPK was not affected by LTB4 treatment. Phosphorylation of Akt was also induced by LTB4 and this effect was blocked by the PI-3 kinase inhibitor wortmannin, which also partially blocked LTB4-stimulated cell proliferation. In conclusion, LTB4 stimulates proliferation of human pancreatic cancer cells through MEK/ERK and PI-3 kinase/Akt pathways, while p38 MPAK and JNK/SAPK are not involved.

Section snippets

Materials and methods

Materials. MEM, penicillin–streptomycin solution, and trypsin–EDTA solution were purchased from Sigma Chemicals (St. Louis, MO). Fetal bovine serum (FBS) was purchased from Altanta Biologicals (Norcross, GA). LTB4 was purchased from Cayman Chemicals (Ann Arbor, MI). The LTB4 receptor antagonist, LY293111, was from the Eli Lilly Research Laboratories (Indianapolis, IN). The MEK1/2 inhibitor, PD098059, was purchased from Calbiochem/Novabiochem International (La Jolla, CA). The MEK inhibitor,

Results and discussion

Our previous studies have demonstrated the expression of both LTB4 receptor sub-types, BLT1 and BLT2, in multiple human pancreatic cancer cells [28], [29]. The selective LTB4 receptor antagonist, LY293111, inhibited proliferation and induced apoptosis in these cells both in vitro and in vivo [29], [30]. In the current studies, we investigated the effect of LTB4 on the proliferation of pancreatic cancer cells and the possible mechanisms involved. The effect of LTB4 on human pancreatic cancer

Acknowledgments

These studies were supported by grants from the NCI SPORE program (P50 CA72712) and the Lustgarten Foundation for Pancreatic Cancer Research. The selective LTB4 receptor antagonist, LY293111, was a kind gift from Drs. Jake Starling and Jerome Fleisch, Eli Lilly Research Laboratories (Indianapolis, IN).

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