Antagonistic L1 Adhesion Molecule Mimetic Compounds Inhibit Glioblastoma Cell Migration In Vitro

Abstract

Cell adhesion molecule L1 is a cell surface glycoprotein that promotes neuronal cell migration, fosters regeneration after spinal cord injury and ameliorates the consequences of neuronal degeneration in mouse and zebrafish models. Counter-indicative features of L1 were found in tumor progression: the more L1 is expressed, the more tumor cells migrate and increase their metastatic potential. L1′s metastatic potential is further evidenced by its promotion of epithelial–mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy. These unfortunate features are indicated by observations that cells that normally do not express L1 are induced to express it when becoming malignant. With the aim to ameliorate the devastating functions of L1 in tumors, we designed an alternative approach to counteract tumor cell migration. Libraries of small organic compounds were screened using the ELISA competition approach similar to the one that we used for identifying L1 agonistic mimetics. Whereas in the former approach, a function-triggering monoclonal antibody was used for screening libraries, we here used the function-inhibiting monoclonal antibody 324 that reduces the migration of neurons. We now show that the L1 antagonistic mimetics anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol inhibit the migration of cultured tumor cells in an L1-dependent manner, raising hopes for therapy.

LINC02323 facilitates development of lung squamous cell carcinoma by miRNA sponge and RBP dysregulation and links to poor prognosis

“… 27 Antagonistic mimetic compounds targeting L1CAM decreases glioblastoma cell migration. 28 Specifically, increased L1CAM expression has been observed in LUSC patients and has a close correlation with an adverse prognosis in LUSC. Functional enrichment analysis showed that the upregulated genes correlated with L1CAM were primarily implicated in various tumor microenvironment remodeling and growth factor‐related pathway, including the EMT process, collagen formation and NRAS pathway.…”

“…LUAD patients with high L1CAM expression in surgically‐resected brain metastases have been reported to have an unfavorable overall survival time 27 . Antagonistic mimetic compounds targeting L1CAM decreases glioblastoma cell migration 28 . Specifically, increased L1CAM expression has been observed in LUSC patients and has a close correlation with an adverse prognosis in LUSC.…”

CDH6 as a prognostic indicator and marker for chemotherapy in gliomas

“…Deforolimus decreases the mammalian target of rapamycin pathway activation and inhibits glioma growth in certain subtypes (Hütt-Cabezas et al, 2013). Anagrelide inhibits GBM cell migration in vitro in an L1-dependent manner (Nagaraj et al, 2022). Vemurafenib demonstrated durable antitumor activity in some patients with BRAF V600 -mutant gliomas (Kaley et al, 2018).…”

Small Organic Compounds Mimicking the Effector Domain of Myristoylated Alanine-Rich C-Kinase Substrate Stimulate Female-Specific Neurite Outgrowth

“…To identify mimetics of ED peptide, we screened small organic compounds as described [ 68 ] using the National Institute of Health Clinical Collection Libraries 1 and 2 (Evotec, Marburg, Germany) and the Natural Compound Library (Selleckchem, Houston, TX, USA) via competition ELISA. In brief, 384-well ELISA plates were coated with 1 µg/mL of antibody against ED.…”