A redox-silent analogue of tocotrienol inhibits cobalt(II) chloride-induced VEGF expression via Yes signaling in mesothelioma cells.
Vascular endothelial growth factor (VEGF) plays a crucial role in tumor angiogenesis and represents an attractive anticancer target. We have previously demonstrated that a redox-silent analogue of α-tocotrienol, 6-O-carboxypropyl-α-tocotrienol (T3E) exhibits potent anti-carcinogenic property in human malignant mesothelioma (MM) cells. However, inhibition of tumor growth by targeting VEGF pathway remains undetermined. In this study, we explored the inhibitory effect of T3E on the paracrine secretion of VEGF in MM cells under mimicked hypoxia by cobalt chloride (CoCl2). In this study we examine whether T3E can suppress the secretion of VEGF in MM cells exposed to mimic hypoxia by cobalt chloride (CoCl2). We found that CoCl2-induced hypoxia treatment leads to increased up-regulated hypoxia-inducible factor-2α (HIF-2α) and subsequently induced the secretion of VEGF in MM cells. This up-regulation activation mainly depended on the activation of Yes, a member of the Src family of kinases. Treatment of hypoxic MM cells with T3E effectively inhibited the secretion of VEGF, On the other hand, T3E inhibited CoCl2-induced gene expression of VEGF due to the inactivation of Yes/HIF-2α signaling. These data suggest that Yes/HIF2-α/VEGF could be a promising therapeutic target of T3E in MM cells.
Graduate School of Life Sciences, Toyo University.
Ayami
A
Sato
Nantiga
N
Virgona
Akira
A
Ando
Masako
M
Ota
Tomohiro
T
Yano
D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003035:Cobalt / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced / Q000378:metabolism; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D051575:Proto-Oncogene Proteins c-yes / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D024508:Tocotrienols / Q000494:pharmacology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D003035:Cobalt; D051575:Proto-Oncogene Proteins c-yes; D024508:Tocotrienols; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C501588:6-O-carboxypropyl-alpha-tocotrienol; C489834:YES1 protein, human; C018021:cobaltous chloride