Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells

Nerve growth factor (NGF) exerts both stimulatory and inhibitory effects on neuronal and certain nonneuronal tumors with the effect based on the type of tumor. We investigated NGF and its receptors (TrkA and p75) in pancreati c cancer cells (PANC-1, MIA-PaCa-2, CAPAN-1, ASPC-1, and T3M4) by reverse t ranscription-PCR, Western blot analysis, NGF ELISA, and growth assays. NGF mRNA was present at comparable levels in all five pancreatic cancer cell li nes. TrkA expression was relatively high in PANC-1 and MIA-PaCa-2 cells and Low in CAPAN-1, ASPC-1, and T3M4 cells. p75 expression was high in PANC-1, MIA-PaCa-2, and T3M4 cells, moderate in CAPAN-1, and low in ASPC-1 cells. By ELISA assay, the intracellular NGF content in all cell lines was similar to 40 pg/10(6) cells. NGF content increased significantly in PANC-1 and MI A-PaCa-2 cells when these cells were cultured with serum-free media, wherea s there was no change in the other cancer cell lines. PANC-1 and MIA-PaCa-2 cells but not the other cell lines released NGF in the culture media. Exog enous NGF stimulated the growth of PANC-1 and MIA-PaCa-2 cells, inhibited t he growth of T3M4 and CAPAN-1 cells in a dose- and time-dependent manner, a nd did not affect the growth of ASPC-1 cells. NGF led to the phosphorylatio n of TrkA, mitogen-activated protein kinase (MAPK), and p38 MAPK but not st ress-activated protein kinase/c-Jun NH2-terminal kinase in PANC-1 and MIA-P aCa-2 cells, In contrast, in the other pancreatic cancer cell Lines none of these kinases were phosphorylated by NGF, In conclusion, the effects of NG F on pancreatic cancer fell growth are dependent on the expression levels a nd the balance of its TrkA and p75 receptors, NGF-induced pancreatic cancer cell growth seems to be mediated through the phosphorylation of TrkA and s ubsequently via MAPK, These results point to a previously unknown autocrine /paracrine pathway in pancreatic cancer, suggesting that NGF-TrkA interacti ons are important factors influencing cell growth and spread in this malign ancy.