Sato Ayami, Virgona Nantiga, Ando Akira, Ota Masako, Yano Tomohiro
Graduate School of Life Sciences, Toyo University.
Biol Pharm Bull. 2014;37(5):865-70. doi: 10.1248/bpb.b13-00846.
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.
血管内皮生长因子（VEGF）在肿瘤血管生成中起关键作用，是一个有吸引力的抗癌靶点。我们之前已经证明，α-生育三烯酚的一种氧化还原沉默类似物，6-O-羧丙基-α-生育三烯酚（T3E）在人恶性间皮瘤（MM）细胞中表现出强大的抗癌特性。然而，通过靶向VEGF通路抑制肿瘤生长的情况仍未确定。在本研究中，我们探讨了T3E在氯化钴（CoCl2）模拟的缺氧条件下对MM细胞中VEGF旁分泌分泌的抑制作用。在本研究中，我们研究了T3E是否能抑制暴露于氯化钴（CoCl2）模拟缺氧环境中的MM细胞中VEGF的分泌。我们发现，CoCl2诱导的缺氧处理导致缺氧诱导因子-2α（HIF-2α）上调增加，随后诱导MM细胞中VEGF的分泌。这种上调激活主要依赖于Src家族激酶成员Yes的激活。用T3E处理缺氧的MM细胞可有效抑制VEGF的分泌，另一方面，由于Yes/HIF-2α信号失活，T3E抑制了CoCl2诱导的VEGF基因表达。这些数据表明，Yes/HIF2-α/VEGF可能是T3E在MM细胞中的一个有前景的治疗靶点。
