Blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in gastric cancer cells.
OBJECTIVE
Hypoxia-inducible factor-1α (HIF-1α) increases transcription of the vascular endothelial growth factor (VEGF) gene. Inhibition of VEGF abolishes VEGF mediated induction of HIF-1α. Recent reports suggested that HIF-1α also mediated the induction of class III β-tubulin (TUBB3) in hypoxia. TUBB3 confers resistance to taxanes. Inhibition of VEGF may decrease the expression of HIF-1α and TUBB3. This study was undertaken to investigate the roles of vascular endothelial growth factor receptor (VEGFR) in gastric cancer cell behavior and to identify methods to overcome paclitaxel resistance in vitro.


METHODS
The protein expression levels of HIF-1α and TUBB3 were measured in human gastric cancer cell lines (AGS) under normoxic and hypoxic conditions. The relationship between TUBB3 and paclitaxel resistance was assessed with small interfering TUBB3 RNA. AGS cells were treated with anti-VEGFR-1, anti-VEGFR-2, placental growth factor (PlGF), bevacizuamb, and paclitaxel.


RESULTS
Hypoxia induced paclitaxel resistance was decreased by knockdown of TUBB3. Induction of HIF-1α and TUBB3 in AGS is VEGFR-1 mediated and PlGF dependent. Hypoxia-dependent upregulation of HIF-1α and TUBB3 was reduced in response to paclitaxel treatment. Expressions of HIF-1α and TUBB3 were most decreased when AGS cells were treated with a combination of paclitaxel and anti-VEGFR-1. AGS cell cytotoxicity was most increased in response to paclitaxel, anti-VEGFR-1, and anti-VEGFR-2.


CONCLUSIONS
We suggest that blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in TUBB3-expressing gastric cancer cells.
Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-eup, Hwasun 519-763, Korea.
Jun-Eul
JE
Hwang
Ji-Hee
JH
Lee
Mi-Ra
MR
Park
Dae-Eun
DE
Kim
Woo-Kyun
WK
Bae
Hyun-Jeong
HJ
Shim
Sang-Hee
SH
Cho
Ik-Joo
IJ
Chung
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000068258:Bevacizumab; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000502:physiology*
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000608036:PGF protein, human; D011257:Pregnancy Proteins; C498585:TUBB3 protein, human; D014404:Tubulin; D000072483:Placenta Growth Factor; D000068258:Bevacizumab; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D017239:Paclitaxel