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Activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase is required for glial cell line-derived neurotrophic factor-induced migration and invasion of pancreatic carcinoma cells.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Veit, Christine Genze, Felicitas Menke, André Hoeffert, Silke Gress, Thomas Matthias Gierschik, Peter Giehl, Klaudia |
| Copyright Year | 2004 |
| Abstract | Pancreatic carcinoma cells exhibit a pronounced tendency to invade along and into intra- and extrapancreatic nerves, even at early stages of the disease. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) has been shown to promote pancreatic cancer cell invasion. Here, we demonstrate that pancreatic carcinoma cell lines, such as PANC-1, expressed the RET and GDNF family receptor alpha receptor components for GDNF and that primary pancreatic tumor samples, derived from carcinomas with regional lymph node metastasis, exhibited marked expression of the mRNA encoding the RET51 isoform. Moreover, GDNF was an efficacious and potent chemoattractant for pancreatic carcinoma cells as examined in in vitro and in vivo model systems. Treatment of PANC-1 cells with GDNF resulted in activation of the monomeric GTPases N-Ras, Rac1, and RhoA, in activation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK) and in activation of the phosphatidylinositol 3-kinase/Akt pathway. Both inhibition of the Ras-Raf-MEK (mitogen-activated protein/ERK kinase)-ERK cascade by either stable expression of dominant-negative H-Ras(N17) or addition of the MEK1 inhibitor PD98059 as well as inhibition of the phosphatidylinositol 3-kinase pathway by LY294002 prevented GDNF-induced migration and invasion of PANC-1 cells. These results demonstrate that pancreatic tumor cell migration and possibly perineural invasion in response to GDNF is critically controlled by activation of the Ras-Raf-MEK-ERK and the phosphatidylinositol 3-kinase pathway. |
| Starting Page | RC104 |
| Ending Page | RC104 |
| Page Count | 1 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/64/15/5291.full.pdf |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/64/15/5291.full.pdf |
| PubMed reference number | 15289335v1 |
| Volume Number | 64 |
| Issue Number | 15 |
| Journal | Cancer research |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 1-Phosphatidylinositol 3-Kinase Anatomic Node Cascade Device Component Chemotactic Factors GDNF protein, human Guanosine Triphosphate Phosphohydrolases LY 294002 Mitogen-Activated Protein Kinases Mitogens Neoplasm Metastasis Neoplasms Neoplastic Cell Nerve Neuroglia PD 98059 Pancreatic Neoplasm Pancreatic carcinoma Proto-Oncogene Proteins c-akt RET gene Set of regional lymph nodes lymph node metastases metastatic pancreas cancer |
| Content Type | Text |
| Resource Type | Article |
