School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Biochim Biophys Acta Mol Cell Res. 2017 Oct;1864(10):1525-1536. doi: 10.1016/j.bbamcr.2017.06.010. Epub 2017 Jun 19.
Angiopoietin-like 4 (ANGPTL4) is a secretory protein that can be cleaved to form an N-terminal and a C-terminal protein. Studies performed thus far have linked ANGPTL4 to several cancer-related and metabolic processes. Notably, several point mutations in the C-terminal ANGPTL4 (cANGPTL4) have been reported, although no studies have been performed that ascribed these mutations to cancer-related and metabolic processes. In this study, we compared the characteristics of tumors with and without wild-type (wt) cANGPTL4 and tumors with cANGPTL4 bearing the T266M mutation (T266M cANGPTL4). We found that T266M cANGPTL4 bound to integrin α5β1 with a reduced affinity compared to wt, leading to weaker activation of downstream signaling molecules. The mutant tumors exhibited impaired proliferation, anoikis resistance, and migratory capability and had reduced adenylate energy charge. Further investigations also revealed that cANGPTL4 regulated the expression of Glut2. These findings may explain the differences in the tumor characteristics and energy metabolism observed with the cANGPTL4 T266M mutation compared to tumors without the mutation.
血管生成素样蛋白 4（ANGPTL4）是一种分泌蛋白，可被切割形成 N 端和 C 端蛋白。迄今为止的研究将 ANGPTL4 与几种与癌症相关的代谢过程联系起来。值得注意的是，已经报道了 C 端 ANGPTL4（cANGPTL4）中的几个点突变，尽管尚未进行将这些突变归因于与癌症相关的代谢过程的研究。在这项研究中，我们比较了具有野生型（wt）cANGPTL4 的肿瘤和没有 cANGPTL4 的肿瘤的特征，以及具有 T266M 突变的 cANGPTL4（T266M cANGPTL4）的肿瘤。我们发现，与 wt 相比，T266M cANGPTL4 与整合素 α5β1 的结合亲和力降低，导致下游信号分子的激活减弱。突变型肿瘤表现出增殖受损、抗失巢凋亡能力和迁移能力降低，以及腺嘌呤核苷酸能量电荷降低。进一步的研究还表明，cANGPTL4 调节 Glut2 的表达。这些发现可以解释与突变型肿瘤相比，cANGPTL4 T266M 突变型肿瘤的肿瘤特征和能量代谢的差异。
