Inhibition of Intermedin (Adrenomedullin 2) Suppresses the Growth of Glioblastoma and Increases the Antitumor Activity of Temozolomide
Inhibition of Intermedin (Adrenomedullin 2) Suppresses the Growth of Glioblastoma and Increases the Antitumor Activity of Temozolomide
复制标题
抑制 Intermedin（肾上腺髓质素 2）可抑制胶质母细胞瘤的生长并增加替莫唑胺的抗肿瘤活性
DOI：
10.1158/1535-7163.mct-20-0619
复制
发表时间：
2021-02-01
影响因子：
5.7
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
--
作者：
Huang, Luping;Wang, Denian;Zhang, Wei
多形性胶质母细胞瘤（GBM; IV级神经胶质瘤）是最恶性的原发性脑肿瘤类型，其特征在于快速增殖和侵袭性生长。中介素（IMD）是属于降钙素基因相关肽家族的内源性肽，并且已经报道在几种类型的癌症中在细胞存活和侵袭性中起重要作用。在本研究中，我们发现IMD的表达水平与胶质瘤的恶性程度呈正相关。IMD在胶质瘤中的表达最高，提示IMD在胶质瘤恶性过程中可能起重要作用。IMD通过促进丝状伪足的形成增加胶质瘤细胞的侵袭能力，这依赖于ERK 1/2的激活。IMD诱导的ERK 1/2磷酸化也促进GBM细胞增殖。此外，IMD增强了GBM细胞的线粒体功能和缺氧诱导的反应。用抗IMD单克隆抗体治疗不仅抑制了异位和原位GBM模型中的肿瘤生长，而且还显著增强了替莫唑胺的抗肿瘤活性。我们的研究可能为GBM细胞侵袭和增殖的机制提供新的见解，并为提高GBM治疗效果提供有效的策略。
Glioblastoma multiforme (GBM; grade IV glioma) is the most malignant type of primary brain tumor and is characterized by rapid proliferation and invasive growth. Intermedin (IMD) is an endogenous peptide belonging to the calcitonin gene-related peptide family and has been reported to play an important role in cell survival and invasiveness in several types of cancers. In this study, we found that the expression level of IMD was positively related to the malignancy grade of gliomas. The highest expression of IMD was found in GBM, indicating that IMD may play an important role in glioma malignancy. IMD increased the invasive ability of glioma cells by promoting filopodia formation, which is dependent on ERK1/2 activation. IMD-induced ERK1/2 phosphorylation also promoted GBM cell proliferation. In addition, IMD enhanced mitochondrial function and hypoxia-induced responses in GBM cells. Treatment with anti-IMD monoclonal antibodies not only inhibited tumor growth in both ectopic and orthotopic models of GBM but also significantly enhanced the antitumor activity of temozolomide. Our study may provide novel insights into the mechanism of GBM cell invasion and proliferation and provide an effective strategy to improve the therapeutic effect of GBM treatments.