Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
J Clin Invest. 2013 Feb;123(2):787-99. doi: 10.1172/JCI64768. Epub 2013 Jan 25.
The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCδ/acid sphingomyelinase (PKCδ/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.
67 千道尔顿层粘连蛋白受体（67LR）是一种在多种癌症中过度表达的层粘连蛋白结合蛋白，包括胆管癌、结直肠癌、宫颈癌和乳腺癌。67LR 在肿瘤细胞的生长和转移以及化疗耐药中发挥着重要作用。在这里，我们表明 67LR 作为一种癌症特异性死亡受体发挥作用。在这个细胞死亡受体途径中，cGMP 通过激活蛋白激酶 Cδ/酸性鞘磷脂酶（PKCδ/ASM）途径引发癌症特异性细胞死亡。此外，cGMP 的上调是绿茶多酚（-）-表没食子儿茶素-3-O-没食子酸酯（EGCG）诱导的 67LR 依赖性细胞死亡的决定速率过程，EGCG 是 67LR 的天然配体。我们发现，环磷酸鸟苷（cGMP）的负调节剂磷酸二酯酶 5（PDE5）在多种癌症中异常表达，并减弱了 67LR 介导的细胞死亡。伐地那非是一种用于治疗勃起功能障碍的 PDE5 抑制剂，它能显著增强 EGCG 激活的 67LR 依赖性细胞凋亡，而不影响正常细胞，并延长了在小鼠异种移植模型中的存活时间。这些结果表明，PDE5 抑制剂可用于提高 cGMP 水平以诱导 67LR 介导的癌症特异性细胞死亡。
