VEGFR3 inhibition chemosensitizes lung adenocarcinoma A549 cells in the tumor-associated macrophage microenvironment through upregulation of p53 and PTEN.

Abstract

In lung adenocarcinoma, loss of p53 and PTEN in tumors are associated with decreased response to chemotherapy and decreased survival. A means to pharmacologically upregulate p53 and PTEN protein expression could improve the prognosis of patients with p53- and PTEN-deficient tumors. In the present study we revealed that vascular endothelial growth factor receptor 3 (VEGFR3) inhibition in lung adenocarcinoma cells was associated with improved expression levels of both p53 and PTEN in the tumor-associated macrophage (TAM) microenvironment. Inhibition of VEGFR3 in lung adenocarcinoma cells was associated with growth arrest and decreased migration and invasion. The upregulation of p53 and PTEN protein expression after VEGFR3 inhibition decreased chemotherapy resistance and improved chemosensitivity in co-cultured A549 cells in which p53 and PTEN expression were decreased. Finally, we demonstrated that TAMs promoted the expression of VEGF-C and its receptor VEGFR3. Western blot analysis revealed the co-cultured A549 cells with TAMs are a primary source of VEGF-C and VEGFR3 in the tumor microenvironment. Our studies revealed that VEGFR3 inhibition may be a pharmacological means to upregulate p53 and PTEN protein expression and improve the outcome of patients with p53- and PTEN-deficient tumors.

• Authors: Ya Li, Yaguang Weng, Liang Zhong, Huimin Chong, Sicheng Chen, Yanting Sun, Wang Li, Qiong Shi
• Journal: Oncology reports (Oncol Rep) Vol. 38 Issue 5 Pg. 2761-2773 (Nov 2017) ISSN: 1791-2431 [Electronic] Greece
• PMID: 29048623 (Publication Type: Journal Article)

Chemical References

• 3-(4-dimethylamino-naphthalen-1-ylmethylene)-1,3-dihydro-indol-2-one
• Indoles
• Naphthalenes
• TP53 protein, human
• Tumor Suppressor Protein p53
• VEGFC protein, human
• Vascular Endothelial Growth Factor C
• Doxorubicin
• FLT4 protein, human
• Vascular Endothelial Growth Factor Receptor-3
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• A549 Cells
• Adenocarcinoma (drug therapy, genetics, metabolism)
• Adenocarcinoma of Lung
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indoles (pharmacology)
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Macrophages (cytology, metabolism)
• Naphthalenes (pharmacology)
• PTEN Phosphohydrolase (genetics)
• THP-1 Cells
• Tumor Microenvironment (drug effects)
• Tumor Suppressor Protein p53 (genetics)
• Up-Regulation
• Vascular Endothelial Growth Factor C (metabolism)
• Vascular Endothelial Growth Factor Receptor-3 (antagonists & inhibitors, metabolism)