Abstract
We previously demonstrated that Annexin A2 (ANXA2) is a pivotal mediator of the pro-oncogenic
features displayed by glioblastoma (GBM) tumors, the deadliest adult brain malignancies,
being involved in cell stemness, proliferation and invasion, thus negatively impacting
patient prognosis. Based on these results, we hypothesized that compounds able to
revert ANXA2-dependent transcriptional features could be exploited as reliable treatments
to inhibit GBM cell aggressiveness by hampering their proliferative and migratory
potential. Transcriptional signatures obtained by the modulation of ANXA2 activity/levels
were functionally mapped through the QUADrATiC bioinformatic tool for compound identification.
Selected compounds were screened by cell proliferation and migration assays in primary
GBM cells, and we identified Homoharringtonine (HHT) as a potent inhibitor of GBM
cell motility and proliferation, without affecting their viability. A further molecular
characterization of the effects displayed by HHT, confirmed its ability to inhibit
a transcriptional program involved in cell migration and invasion. Moreover, we demonstrated
that the multiple antitumoral effects displayed by HHT are correlated to the inhibition
of a platelet derived growth factor receptor α (PDGFRα)-dependent intracellular signaling
through the impairment of Signal transducer and activator of transcription 3 (STAT3)
and Ras homolog family member A (RhoA) axes. Our results demonstrate that HHT may
act as a potent inhibitor of cancer cell proliferation and invasion in GBM, by hampering
multiple PDGFRα-dependent oncogenic signals transduced through the STAT3 and RhoA
intracellular components, finally suggesting its potential transferability for achieving
an effective impairment of peculiar GBM hallmarks.
Abbreviations:
5-ALA (5-aminolevulinic acid), ANXA2 (Annexin A2), AZA (5′-Azacytidine), bFGF (basic Fibroblast Growth Factor), BOR (Bortezomib), CML (Chronic Myeloid Leukemia), DEGs (Differentially Expressed Genes), DIG (Digitoxin), ECM (Extracellular Matrix), EGF (Epidermal Growth Factor), EMT (Epithelial to Mesenchymal Transition), FA (Focal Adhesion), FBS (Foetal Bovine Serum), FDA (Food and Drug Administration), GBM (Glioblastoma), GEP (Gene Expression Profile), GI50 (Growth Inhibition 50), gw (gestational weeks), HHT (Homoharringtonine), hpi (hours post-injection), MFI (Mean Fluorescence Intensity), NIC (Niclosamide), OUA (Ouabain), PDGFRα (Platelet Derived Growth Factor Receptor α), PRO (Probenecid), PVDF (polyvinylidene difluoride), S.E.M. (Standard Error of the Mean), TMZ (Temozolomide), WB (Western Blot)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Temozolomide in malignant gliomas: current use and future targets.Cancer Chemother Pharmacol. 2009; 64: 647-655
- Therapy for glioblastoma: is it working?.Drug Discov Today. 2019; 24: 1193-1201
- Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.N Engl J Med. 2005; 352: 987-996
- Management of glioblastoma: state of the art and future directions.CA Cancer J Clin. 2020; 70: 299-312
- Mechanisms regulating glioma invasion.Cancer Lett. 2015; 362: 1-7
- Phenotypic and functional characterization of Glioblastoma cancer stem cells identified through 5-aminolevulinic acid-assisted surgery [corrected].J Neurooncol. 2014; 116: 505-513
- Annexin II: a mediator of the plasmin/plasminogen activator system.Trends Cardiovasc Med. 1999; 9: 128-138
- Annexin 2A sustains glioblastoma cell dissemination and proliferation.Oncotarget. 2016; 7: 54632-54649
- Annexin A2 regulates angiogenesis and invasion phenotypes of malignant glioma.Brain Tumor Pathol. 2015; 32: 184-194
- Annexin A2 silencing induces G2 arrest of non-small cell lung cancer cells through p53-dependent and -independent mechanisms.J Biol Chem. 2012; 287: 32512-32524
- Annexin A2 promotes glioma cell invasion and tumor progression.J Neurosci. 2011; 31: 14346-14360
- Knockdown of annexin 2 decreases migration of human glioma cells in vitro.Neuropathol Appl Neurobiol. 2006; 32: 271-277
- The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease.Science. 2006; 313: 1929-1935
- Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data.Cell Death Dis. 2015; 6: e1753
- Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma.Oncotarget. 2015; 6: 21718-21729
- Integrative analysis of gene expression and DNA methylation through one-class logistic regression machine learning identifies stemness features in medulloblastoma.Mol Oncol. 2019; 13: 2227-2245
- QUADrATiC: scalable gene expression connectivity mapping for repurposing FDA-approved therapeutics.BMC Bioinformatics. 2016; 17: 198
- The annexin A2/S100A10 system in health and disease: emerging paradigms.J Biomed Biotechnol. 2012; 2012406273
- Isolation and expansion of regionally defined human glioblastoma cells in vitro.Curr Protoc Stem Cell Biol. 2011; (Chapter 3:Unit 3.4)
- Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma.Stem Cells. 2010; 28: 851-862
- Panchision DM. Oxygen tension controls the expansion of human CNS precursors and the generation of astrocytes and oligodendrocytes.Mol Cell Neurosci. 2007; 35: 424-435
- Isolation and characterization of neural progenitor cells from post-mortem human cortex.J Neurosci Res. 2003; 74: 838-851
- Studies of combinations of antibiotics in vitro and in experimental infections in mice.Bull Johns Hopkins Hosp. 1952; 90: 149-169
- A high-throughput drug combination screen of targeted small molecule inhibitors in cancer cell lines.Sci Data. 2019; 6: 237
- Significance analysis of microarrays applied to the ionizing radiation response.Proc Natl Acad Sci U S A. 2001; 98: 5116-5121
- Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.Proc Natl Acad Sci U S A. 2005; 102: 15545-15550
- Stages of embryonic development of the zebrafish.Dev Dyn. 1995; 203: 253-310
- Targeting annexin A2 reduces tumorigenesis and therapeutic resistance of nasopharyngeal carcinoma.Oncotarget. 2015; 6: 26946-26959
- Annexin A2 regulates glioma cell proliferation through the STAT3cyclin D1 pathway.Oncol Rep. 2019; 42: 399-413
- Anticancer effects of niclosamide in human glioblastoma.Clin Cancer Res. 2013; 19: 4124-4136
- Contributions of hepatic and intestinal metabolism to the disposition of niclosamide, a repurposed drug with poor bioavailability.Drug Metab Dispos. 2019; 47: 756-763
- Preclinical testing of a novel Niclosamide Stearate Prodrug Therapeutic (NSPT) shows efficacy against osteosarcoma.Mol Cancer Ther. 2020; 19: 1448-1461
- Homoharringtonine: an effective new natural product in cancer chemotherapy.Bull Cancer. 1995; 82: 987-995
- Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells.Sci Rep. 2015; 5: 8477
- The role of STAT3 in glioblastoma progression through dual influences on tumor cells and the immune microenvironment.Mol Cell Endocrinol. 2017; 451: 53-65
- Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis.Proc Natl Acad Sci U S A. 2001; 98: 7319-7324
- Platelet-derived growth factor receptor-alpha is a key determinant of smooth muscle alpha-actin filaments in bone marrow-derived mesenchymal stem cells.Int J Biochem Cell Biol. 2007; 39: 379-391
- Supratentorial malignant glioma: patterns of recurrence and implications for external beam local treatment.Int J Radiat Oncol Biol Phys. 1992; 24: 55-57
- Prognostic value of residual fluorescent tissue in glioblastoma patients after gross total resection in 5-aminolevulinic Acid-guided surgery.Neurosurgery. 2013; 72 (discussion 20-1): 915-920
- Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias.Neurosurgery. 2008; 62 (discussion -76): 564-576
- Annexin A2 (ANX A2): an emerging biomarker and potential therapeutic target for aggressive cancers.Int J Cancer. 2019; 144: 2074-2081
- Annexin A2 is required for the early steps of cytokinesis.EMBO Rep. 2015; 16: 481-489
- The protein-tyrosine kinase substrate, calpactin I heavy chain (p36), is part of the primer recognition protein complex that interacts with DNA polymerase alpha.J Biol Chem. 1991; 266: 5169-5176
- Recent advances in the development of antineoplastic agents derived from natural products.Drugs. 2015; 75: 1993-2016
- Homoharringtonine for the treatment of chronic myelogenous leukemia.Expert Opin Pharmacother. 2008; 9: 1029-1037
- Omacetaxine mepesuccinate (synribo) - newly launched in chronic myeloid leukemia.Expert Opin Pharmacother. 2013; 14: 1977-1986
- Homoharringtonine induced immune alteration for an Efficient Anti-tumor Response in Mouse Models of Non-small Cell Lung Adenocarcinoma Expressing Kras Mutation.Sci Rep. 2018; 8: 8216
- Homoharringtonine, an approved anti-leukemia drug, suppresses triple negative breast cancer growth through a rapid reduction of anti-apoptotic protein abundance.Am J Cancer Res. 2019; 9: 1043-1060
- Rhabdoid tumors are sensitive to the protein-translation inhibitor homoharringtonine.Clin Cancer Res. 2020; 26: 4995-5006
- Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated beta-catenin loss in hepatocellular carcinoma.Cell Death Dis. 2020; 11: 632
- Homoharringtonine inhibits melanoma cells proliferation in vitro and vivo by inducing DNA damage, apoptosis, and G2/M cell cycle arrest.Arch Biochem Biophys. 2021; 700108774
- Central nervous system (CNS) penetration of homoharringtonine (HHT).J Neurooncol. 1987; 5: 77-81
- Phase II study of homoharringtonine in patients with recurrent primary malignant central nervous system tumors.J Neurooncol. 1990; 9: 159-163
- Anxa2 binds to STAT3 and promotes epithelial to mesenchymal transition in breast cancer cells.Oncotarget. 2015; 6: 30975-30992
- RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway.Breast Cancer Res Treat. 2015; 153: 263-275
- Annexin A2-STAT3-Oncostatin M receptor axis drives phenotypic and mesenchymal changes in glioblastoma.Acta Neuropathol Commun. 2020; 8: 42
- In vitro wound healing of tumor cells: inhibition of cell migration by selected cytotoxic alkaloids.BMC Pharmacol Toxicol. 2019; 20: 4
Article Info
Publication History
Published online: July 01, 2022
Accepted:
June 27,
2022
Received in revised form:
June 24,
2022
Received:
February 3,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Elena Porcù and Francesca Maule contributed equally to this work.
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
