αB-Crystallin, an Effector of Unfolded Protein Response, Confers Anti-VEGF Resistance to Breast Cancer via Maintenance of Intracrine VEGF in Endothelial Cells (Retracted article. See vol. 20, pg. 1179, 2022)

αB-Crystallin, an Effector of Unfolded Protein Response, Confers Anti-VEGF Resistance to Breast Cancer via Maintenance of Intracrine VEGF in Endothelial Cells (Retracted article. See vol. 20, pg. 1179, 2022)

Effective inhibition of angiogenesis targeting the tumor endothelial cells requires identification of key cellular and molecular mechanisms associated with survival of vasculatures within the tumor microenvironment. Intracellular autocrine (intracrine) VEGF production by endothelial cells plays a critical role on the vasculature homeostasis. In vitro breast cancer cell-stimulated activation of the unfolded protein response (UPR) of the endothelial cells contributes to maintenance of the intracrine VEGF levels in the endothelial cells through the upregulation of a previous undescribed downstream effector- alpha B-crystallin (CRYAB). siRNA-mediated knockdown of two major UPR proteins-inositol requiring kinase 1 and ATF6, led to attenuated CRYAB expression of the endothelial cells. Finally, inhibition of CRYAB blocked the breast cancer cell-stimulated increase in the endogenous VEGF levels of the endothelial cells. A VEGF limited proteolysis assay further revealed that CRYAB protected VEGF for proteolytic degradation. Here, we report that the molecular chaperone-CRYAB was significantly increased and colocalized with tumor vessels in a breast cancer xenograft. Specifically, neutralization of VEGF induced higher levels of CRYAB expression in the endothelial cells cocultured with MDA-MB-231 or the breast cancer xenograft with a significant survival benefit. However, knockdown of CRYAB had a greater inhibitory effect on endothelial survival. These findings underscore the importance of defining a role for intracrine VEGF signaling in sustaining aberrant tumor angiogenesis and strongly implicate UPR/CRYAB as dichotomous parts of a crucial regulation pathway for maintaining intracrine VEGF signaling. Mol Cancer Res; 9(12); 1632-43. (C) 2011 AACR.

针对肿瘤内皮细胞有效地抑制血管生成需要识别与肿瘤微环境内脉管系统存活相关的关键细胞和分子机制。内皮细胞产生的细胞内自分泌（胞内分泌）血管内皮生长因子（VEGF）在脉管系统稳态中起关键作用。体外乳腺癌细胞刺激内皮细胞的未折叠蛋白反应（UPR）激活，通过上调一种先前未描述的下游效应物αB - 晶状体蛋白（CRYAB），有助于维持内皮细胞内的胞内分泌VEGF水平。小干扰RNA（siRNA）介导的两种主要UPR蛋白——需肌醇激酶1和活化转录因子6（ATF6）的敲低，导致内皮细胞的CRYAB表达减弱。最后，CRYAB的抑制阻断了乳腺癌细胞刺激的内皮细胞内源性VEGF水平的升高。一种VEGF有限蛋白水解试验进一步揭示CRYAB保护VEGF免受蛋白水解降解。在此，我们报道在乳腺癌异种移植模型中，分子伴侣CRYAB显著增加并与肿瘤血管共定位。具体而言，在与MDA - MB - 231共培养的内皮细胞或乳腺癌异种移植中，中和VEGF诱导更高水平的CRYAB表达，并具有显著的生存益处。然而，CRYAB的敲低对内皮细胞存活具有更强的抑制作用。这些发现强调了确定胞内分泌VEGF信号在维持异常肿瘤血管生成中的作用的重要性，并强烈暗示UPR/CRYAB是维持胞内分泌VEGF信号的关键调节途径的两个部分。《分子癌症研究》；9(12)；1632 - 1643。（C）2011美国癌症研究协会。