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(Adrenomedullin 2) Suppresses the Growth of Glioblastoma And Published OnlineFirst December 9, 2020; DOI: 10.1158/1535-7163.MCT-20-0619 MOLECULAR CANCER THERAPEUTICS | SMALL MOLECULE THERAPEUTICS Inhibition of Intermedin (Adrenomedullin 2) Suppresses the Growth of Glioblastoma and Increases the Antitumor Activity of Temozolomide A C Luping Huang1, Denian Wang2, Zhongxue Feng1, Huan Zhao1, Fei Xiao3, Yong’gang Wei4, Heng Zhang5, Hongyu Li6, Lingmiao Kong1, Min Li1, Fei Liu4, Haili Zhang4, and Wei Zhang1 ABSTRACT ◥ Glioblastoma multiforme (GBM; grade IV glioma) is the by promoting filopodia formation, which is dependent on most malignant type of primary brain tumor and is character- ERK1/2 activation. IMD-induced ERK1/2 phosphorylation also ized by rapid proliferation and invasive growth. Intermedin promoted GBM cell proliferation. In addition, IMD enhanced (IMD)isanendogenouspeptidebelonging to the calcitonin mitochondrial function and hypoxia-induced responses in gene-related peptide family and has been reported to play an GBM cells. Treatment with anti-IMD monoclonal antibodies important role in cell survival and invasiveness in several not only inhibited tumor growth in both ectopic and orthotopic types of cancers. In this study, we found that the expression models of GBM but also significantly enhanced the antitumor level of IMD was positively related to the malignancy grade of activity of temozolomide. Our study may provide novel insights gliomas. The highest expression of IMD was found in GBM, into the mechanism of GBM cell invasion and proliferation and indicating that IMD may play an important role in glioma provide an effective strategy to improve the therapeutic effect of malignancy. IMD increased the invasive ability of glioma cells GBM treatments. Introduction radiotherapy, and chemotherapy, but the outcomes are often poor. The 2-year survival rate of GBM is only 10% to 25%, and the average Glioma is the most common tumor in the central nervous survival time after diagnosis is only 12 to 15 months (1, 3). Therefore, system (1–4). Grades I and II gliomas are low-grade gliomas, which new therapeutic targets and more effective therapeutic methods have are relatively histologically benign and have a good prognosis, become urgent needs for GBM treatment. although there is still a chance of recurrence or increased malignancy. Intermedin [IMD; also named Adrenomedullin 2 (ADM2)] is a High-grade gliomas account for more than two-thirds of all intracra- member of the calcitonin gene-related peptide family (5, 6). Members nial primary malignancies (1, 4). Grade IV glioma, also called glio- of this family are widely expressed throughout the body and play blastoma multiforme (GBM), is the most malignant type of primary important biological roles, including mediating calcium regulation (7), brain tumor and is characterized by rapid cell proliferation, invasive glucose metabolism (8), and cardiovascular functions (9). Previous growth to surrounding tissues, abundant neovascularization, and studies on IMD have mainly focused on its roles in mediating repeated recurrence (1–4). The main treatments for GBM are surgery, cardiovascular functions (9, 10, 11), but the role of IMD in tumors has recently been discerned (12–15). The first report about IMD and tumors was published in 2008; Morimoto and colleagues reported that 1 Department of Critical Care Medicine, State Key Laboratory of Biotherapy and the expression of IMD was elevated in malignant adrenal tumors (14). Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan, China. 2Department of Respiratory In addition, the level of IMD in peripheral blood was found to and Critical Care Medicine, State Key Laboratory of Biotherapy, West China be elevated in patients with breast cancer and prostate cancer, and Hospital, Sichuan University, Sichuan, China. 3Department of Intensive Care Unit high IMD levels were correlated with poor survival outcomes in of Gynecology and Obstetrics, West China Second University Hospital, Sichuan these patients with cancer (12, 13). IMD is also overexpressed in 4 University, Sichuan, China. Department of Liver Surgery, West China Hospital, hepatocellular carcinoma and plays important roles in cancer cell Sichuan University, Sichuan, China. 5Department of Neurosurgery, West China 6 proliferation and survival (15). Moreover, IMD is expressed in the Hospital, Sichuan University, Sichuan, China. Liver Transplantation Center, fi Beijing Friendship Hospital, Capital Medical University, Beijing, China. human brain and pituitary gland (16). According to these ndings, we hypothesized that IMD may mediate glioma occurrence and Note: Supplementary data for this article are available at Molecular Cancer malignancy. Therapeutics Online (http://mct.aacrjournals.org/). In this study, we sought to examine the expression of IMD in glioma L. Huang, D. Wang, Z. Feng, H. Zhao, F. Xiao, Y. Wei, and H. Li contributed equally samples, to investigate the role of IMD in tumor invasiveness and to this article. growth, to elucidate the underlying mechanisms, and to test whether Corresponding Author: Wei Zhang, Department of Critical Care Medicine, State blockade of IMD has an antitumor effect. Here, we showed that a higher Key Laboratory of Biotherapy, West China Hospital, Sichuan University and IMD level was correlated with a higher grade of glioma. The highest Collaborative Innovation Center for Biotherapy, No. 1, Ke Yuan 4th Road, Chengdu 610041, China. Phone: 86-28-85164092; Fax: 86-28-85164092; E-mail: expression of IMD was found in GBM, indicating that IMD may play [email protected] important roles in the malignancy of gliomas. IMD increased the invasive ability of glioma cells by promoting filopodia formation, which Mol Cancer Ther 2021;20:284–95 is dependent on ERK1/2 activation. In addition, IMD was found to be doi: 10.1158/1535-7163.MCT-20-0619 involved in mitochondrial function and hypoxia-induced responses in Ó2020 American Association for Cancer Research. GBM cells. Blockade of IMD inhibited the growth of GBM and AACRJournals.org | 284 Downloaded from mct.aacrjournals.org on October 2, 2021. © 2021 American Association for Cancer Research. Published OnlineFirst December 9, 2020; DOI: 10.1158/1535-7163.MCT-20-0619 Anti-IMD Inhibits GBM Growth and Increases TMZ Activity significantly enhanced the antitumor activity of temozolomide (TMZ). (1:200), and signals were developed by incubating the sections with Our study may provide novel insights into the mechanism of GBM cell DAB chromogen (brown) and counterstaining with hematoxylin invasion and provide a new therapeutic strategy for GBM. (blue). IMD expression was scored as follows: 0 points, no positive cells; 1 point, <10% positive cells; 2 points, 10% to 50% positive cells; 3 points, 51% to 80% positive cells; and 4 points, >80% positive cells. Materials and Methods The staining intensity was rated as follows: 1 point, weak staining; 2 Cells and culture conditions points, moderate intensity; and 3 points, strong intensity. Points were C6 (rat) and U251 (human) GBM cell lines were from ATCC and added to generate overall scores. The H&E staining was scored by two routinely cultured in complete DMEM. The primary GBM tumors blinded observers. were collected from the surgical samples. The resected tumor tissues from patients with GBM at West China Hospital were mechanically Transwell assay digested and temporarily cultured in vitro. The cells were then Five thousand cells were seeded on Matrigel-coated upper chamber collected and mixed 1:1 with Matrigel (Corning) and injected subcu- (transwell inserts, pore size: 3.0 mmol/L; Millipore) of the 24-well plates taneously into SCID mice. The xenografts were digested into single cell and incubated at 37 C, 5% CO2. After incubated for 24 hours, the cells suspensions using enzymatic digestion [12500 U of Collagenase II and that transmigrated to the lower surface of the membrane were stained 12500 U of Collagenase IV (Sigma) in serum-free DMEM]. The cells with CFSE, fixed with 4% PFA. The total number of migrated cells was were established in May 2017, authenticated using PowerPlex 18D counted under microscope. The experiment was performed in dupli- System (Promega Corporation), and the last time these cells were cate wells and repeated three times independently. tested was December 2019. The cell lines were routinely grown in DMEM supplemented with 10% FBS at 37 C and 5% CO2. Western blot analysis Cell extracts were separated by SDS-PAGE and electro-transferred Antibodies and reagents onto polyvinylidene fluoride membranes, and blocked in 5% nonfat The IMD mature peptide was synthesized and purchased from milk in Tris-buffered saline/0.01% Tween 20 for 2 hours. Blots were Shinegene. The Rabbit–antihuman IMD polyclonal antibody was incubated at 4C in Tris-buffered saline with primary antibody customized and purified by Abgent Co. (17). Antibodies for total- (dilution according to the manufacturer’s instruction), followed by ERK1/2 (#4695) and p-ERK1/2 (#4370) were from Cell Signaling 1 hour incubation with horseradish peroxidase-conjugated secondary Technology; antibody for Ki-67 (Catalog No. RM-9106) was from antibody and detected by a Chemiluminescence Kit (Millipore; Thermo Fisher Scientific; Alexa Fluor 568-conjugated phalloidin Catalog No. WBKLS0100). (A12380) was from Invitrogen and Thermo Fisher Scientific; PD98059 was from Sigma-Aldrich and Merck. Fluorescent microscopy and filopodia quantification Cells were cultured on coverslip, fixed with 4% PFA, and stained The anti-IMD mAb
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