Intracrine VEGF Signaling Mediates the Activity of Prosurvival Pathways in Human Colorectal Cancer Cells
| Autor: | Xiang Cang Ye, Rajat Bhattacharya, Delphine R. Boulbes, Fan Fan, Madonna McManus, Xia Ling, Rui Wang, Lee M. Ellis |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Vascular Endothelial Growth Factor A Cancer Research Intracrine Antimetabolites Antineoplastic Colorectal cancer Blotting Western Fluorescent Antibody Technique Apoptosis Article 03 medical and health sciences Paracrine signalling 0302 clinical medicine Tumor Cells Cultured Medicine Humans Phosphorylation Autocrine signalling Protein kinase B Cell Proliferation business.industry Cell growth Cancer medicine.disease Vascular endothelial growth factor A 030104 developmental biology Receptors Vascular Endothelial Growth Factor Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Immunology Cancer research Fluorouracil business Colorectal Neoplasms Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Cancer research. 76(10) |
| ISSN: | 1538-7445 |
| Popis: | The effects of vascular endothelial growth factor-A (VEGF-A/VEGF) and its receptors on endothelial cells function have been studied extensively, but their effects on tumor cells are less well defined. Studies of human colorectal cancer cells where the VEGF gene has been deleted suggest an intracellular role of VEGF as a cell survival factor. In this study, we investigated the role of intracrine VEGF signaling in colorectal cancer cell survival. In human colorectal cancer cells, RNAi-mediated depletion of VEGF decreased cell survival and enhanced sensitivity to chemotherapy. Unbiased reverse phase protein array studies and subsequent validation experiments indicated that impaired cell survival was a consequence of disrupted AKT and ERK1/2 (MAPK3/1) signaling, as evidenced by reduced phosphorylation. Inhibition of paracrine or autocrine VEGF signaling had no effect on phospho-AKT or phospho-ERK1/2 levels, indicating that VEGF mediates cell survival via an intracellular mechanism. Notably, RNAi-mediated depletion of VEGF receptor VEGFR1/FLT1 replicated the effects of VEGF depletion on phospho-AKT and phospho-ERK1/2 levels. Together, these studies show how VEGF functions as an intracrine survival factor in colorectal cancer cells, demonstrating its distinct role in colorectal cancer cell survival. Cancer Res; 76(10); 3014–24. ©2016 AACR. |
| Databáze: | OpenAIRE |
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