Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan 330-714, Republic of Korea.
Department of Molecular Bioscience, College of Biomedical Science, Kangwon National University, Chuncheon 200-701, Republic of Korea.
Cancer Lett. 2014 Feb 28;343(2):210-6. doi: 10.1016/j.canlet.2013.10.037. Epub 2013 Nov 16.
In the present study, we report the regulatory effects and molecular mechanisms of integrin α3β1-binding tissue inhibitor of metalloproteinases-2 (TIMP-2) 18-mer peptide (peptide 9) on proliferation, migration and tubular formation in human umbilical vein endothelial cells. Peptide 9 markedly inhibits vascular endothelial growth factor-A-stimulated cell proliferation. This anti-proliferative activity of peptide 9 is mediated by cAMP/protein kinase A (PKA)-dependent induction of p27(Kip1) expression as evidenced by using adenylate cyclase inhibitor SQ22536 or PKA inhibitor H89. Peptide 9-mediated inhibition of endothelial cell migration and tubular formation is also dependent on cAMP/PKA activity. Collectively, our findings clearly show the pharmacological roles and action mechanism of peptide 9 in regulating angiogenic responses through cAMP/PKA activity, and support further development as a potential therapeutics for the treatment of angiogenesis-related disorders including cancer.
在本研究中，我们报告了整合素 α3β1 结合的基质金属蛋白酶组织抑制剂-2（TIMP-2）18 肽（肽 9）对人脐静脉内皮细胞增殖、迁移和管状形成的调节作用及其分子机制。肽 9 显著抑制血管内皮生长因子-A 刺激的细胞增殖。肽 9 的这种抗增殖活性是通过 cAMP/蛋白激酶 A（PKA）依赖性诱导 p27(Kip1) 表达介导的，这一点可以通过使用腺苷酸环化酶抑制剂 SQ22536 或 PKA 抑制剂 H89 得到证明。肽 9 介导的内皮细胞迁移和管状形成的抑制也依赖于 cAMP/PKA 活性。总之，我们的研究结果清楚地表明，肽 9 通过 cAMP/PKA 活性调节血管生成反应的药理作用和作用机制，并支持进一步开发作为治疗包括癌症在内的与血管生成相关疾病的潜在治疗药物。
