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Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells
1Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, Switzerland.
Abstract:
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 pancreatic cancer cells (PANC-1, MIA-PaCa-2, CAPAN-1, ASPC-1, and T3M4) by reverse transcription-PCR, Western blot analysis, NGF ELISA, and growth assays. NGF mRNA was present at comparable levels in all five pancreatic cancer cell lines. 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 approximately 40 pg/10(6) cells. NGF content increased significantly in PANC-1 and MIA-PaCa-2 cells when these cells were cultured with serum-free media, whereas 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. Exogenous NGF stimulated the growth of PANC-1 and MIA-PaCa-2 cells, inhibited the growth of T3M4 and CAPAN-1 cells in a dose- and time-dependent manner, and did not affect the growth of ASPC-1 cells. NGF led to the phosphorylation of TrkA, mitogen-activated protein kinase (MAPK), and p38 MAPK but not stress-activated protein kinase/c-Jun NH2-terminal kinase in PANC-1 and MIA-PaCa-2 cells. In contrast, in the other pancreatic cancer cell lines none of these kinases were phosphorylated by NGF. In conclusion, the effects of NGF on pancreatic cancer cell growth are dependent on the expression levels and the balance of its TrkA and p75 receptors. NGF-induced pancreatic cancer cell growth seems to be mediated through the phosphorylation of TrkA and subsequently via MAPK. These results point to a previously unknown autocrine/paracrine pathway in pancreatic cancer, suggesting that NGF-TrkA interactions are important factors influencing cell growth and spread in this malignancy.
Insights
Nerve growth factor (NGF) has varied effects on pancreatic cancer cell growth, depending on receptor expression. NGF promotes growth in some cells via TrkA and MAPK pathways, while inhibiting others, revealing a novel autocrine/paracrine signaling role.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Nerve growth factor (NGF) influences neuronal and non-neuronal tumors.
- Its role in pancreatic cancer, particularly concerning its receptors TrkA and p75, requires detailed investigation.
Purpose of the Study:
- To investigate the expression and function of NGF and its receptors (TrkA, p75) in human pancreatic cancer cell lines.
- To elucidate the signaling pathways involved in NGF-mediated effects on pancreatic cancer cell growth.
Main Methods:
- Reverse transcription-PCR and Western blot analysis for gene and protein expression.
- NGF Enzyme-Linked Immunosorbent Assay (ELISA) for NGF quantification.
- Cell growth assays and kinase phosphorylation studies.
Main Results:
- NGF mRNA was detected in all tested pancreatic cancer cell lines.
- Differential expression of TrkA and p75 receptors was observed across cell lines.
- Exogenous NGF differentially affected cell growth: stimulating PANC-1/MIA-PaCa-2 and inhibiting T3M4/CAPAN-1.
- NGF induced TrkA, MAPK, and p38 MAPK phosphorylation in responsive cell lines.
Conclusions:
- Pancreatic cancer cell growth responses to NGF are contingent on the balance and expression levels of TrkA and p75 receptors.
- NGF-induced growth stimulation in certain pancreatic cancer cells is mediated by TrkA phosphorylation and subsequent MAPK activation.
- These findings suggest an autocrine/paracrine NGF-TrkA signaling pathway influencing pancreatic cancer progression.
