Targeting CXCR4 to suppress glioma‐initiating cells and chemoresistance in glioma

Glioma initiating cells (GICs), also known as glioma stem cells, display the capacity to recapitulate the functional diversity within the tumor. Despite the great progress achieved over the last decades, defining the key molecular regulators of GICs has represented a major obstacle in this field. In our study, data from The Cancer Genome Atlas database illustrated a relationship between C‐X‐C motif chemokine receptor 4 (CXCR4) expression and the survival of glioma patients. Mechanistically, we further indicated that CXCR4 mediated the upregulation of Kruppel like factor 5 (KLF5), a zinc‐finger‐containing transcription factor, to facilitate the proliferation of GICs. What's more, CXCR4 also enhanced the chemoresistance through KLF5/Bcl2‐like 12 (BCl2L12) in glioma. The elevated expression of KLF5 and BCL2L12 induced by CXCR4 was dependent on phosphoinositide 3‐kinases (PI3K)/serine/threonine kinase (AKT) signaling. Importantly, combined application of temozolomide and a CXCR4 inhibitor efficiently reversed CXCR4 mediated drugs resistance and improved anticancer effects in vivo. Collectively, our findings confirmed that CXCR4 promoted GICs proliferation via the KLF5/BCL2L12 dependent pathway, which may enrich the understanding of GICs and help drive the design of efficacious therapeutic strategies.

[1]  U. Pastorino,et al.  A novel CXCR4 antagonist counteracts paradoxical generation of cisplatin-induced pro-metastatic niches in lung cancer , 2021, Molecular therapy : the journal of the American Society of Gene Therapy.

[2]  Ceshi Chen,et al.  The roles and regulation of the KLF5 transcription factor in cancers , 2021, Cancer science.

[3]  Lily Yang,et al.  Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer , 2021, Nature Communications.

[4]  L. Boise,et al.  TGF-β causes Docetaxel resistance in Prostate Cancer via the induction of Bcl-2 by acetylated KLF5 and Protein Stabilization , 2020, Theranostics.

[5]  Xingchen Peng,et al.  Observation versus radiotherapy with or without temozolomide in postoperative WHO grade II high-risk low-grade glioma: a retrospective cohort study , 2020, Neurosurgical Review.

[6]  A. Ben-Baruch,et al.  Beyond Cell Motility: The Expanding Roles of Chemokines and Their Receptors in Malignancy , 2020, Frontiers in Immunology.

[7]  Hua Zhou,et al.  Arg kinase mediates CXCL12/CXCR4-induced invadopodia formation and invasion of glioma cells. , 2020, Experimental cell research.

[8]  G. Hoxhaj,et al.  The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism , 2019, Nature Reviews Cancer.

[9]  M. Shoshan,et al.  A Shifty Target: Tumor-Initiating Cells and Their Metabolism , 2019, International journal of molecular sciences.

[10]  Zhongwei Xu,et al.  JMJD3 promotes the epithelial-mesenchymal transition and migration of glioma cells via the CXCL12/CXCR4 axis , 2019, Oncology letters.

[11]  Lihua Lu,et al.  Crocin inhibits the migration, invasion, and epithelial‐mesenchymal transition of gastric cancer cells via miR‐320/KLF5/HIF‐1α signaling , 2019, Journal of cellular physiology.

[12]  Xuejun Yang,et al.  Notch1 signaling pathway promotes invasion, self-renewal and growth of glioma initiating cells via modulating chemokine system CXCL12/CXCR4 , 2019, Journal of Experimental & Clinical Cancer Research.

[13]  Yuelong Wang,et al.  CXCL12/CXCR4 promotes proliferation, migration, and invasion of adamantinomatous craniopharyngiomas via PI3K/AKT signal pathway , 2019, Journal of cellular biochemistry.

[14]  B. Fazi,et al.  The Expression of the Chemokine CXCL14 Correlates with Several Aggressive Aspects of Glioblastoma and Promotes Key Properties of Glioblastoma Cells , 2019, International journal of molecular sciences.

[15]  Xingchen Peng,et al.  Radiotherapy versus radiotherapy combined with temozolomide in high-risk low-grade gliomas after surgery: study protocol for a randomized controlled clinical trial , 2019, Trials.

[16]  Christopher M. Jackson,et al.  Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment , 2019, Journal of Neuro-Oncology.

[17]  D. Dávila,et al.  Targeting Glioma Initiating Cells with A combined therapy of cannabinoids and temozolomide , 2018, Biochemical pharmacology.

[18]  R. Nibbs,et al.  A guide to chemokines and their receptors , 2018, The FEBS journal.

[19]  Jian Zheng,et al.  The Effect of MCM3AP-AS1/miR-211/KLF5/AGGF1 Axis Regulating Glioblastoma Angiogenesis , 2018, Front. Mol. Neurosci..

[20]  Shucheng Ma,et al.  MicroRNA-182 targets protein phosphatase 1 regulatory inhibitor subunit 1C in glioblastoma , 2017, Oncotarget.

[21]  Rong Liu,et al.  YD277 Suppresses Triple-Negative Breast Cancer Partially Through Activating the Endoplasmic Reticulum Stress Pathway , 2017, Theranostics.

[22]  Tala,et al.  Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation , 2017, Cell Discovery.

[23]  Thomas C. Chen,et al.  Tumor vasculature and glioma stem cells: Contributions to glioma progression. , 2016, Cancer letters.

[24]  S. Kesari,et al.  Further understanding of the pathology of glioma: implications for the clinic , 2016, Expert review of neurotherapeutics.

[25]  Chao Dong,et al.  Mifepristone Suppresses Basal Triple-Negative Breast Cancer Stem Cells by Down-regulating KLF5 Expression , 2016, Theranostics.

[26]  A. Luster,et al.  The chemokine system in innate immunity. , 2015, Cold Spring Harbor perspectives in biology.

[27]  S. Nimmagadda,et al.  The Intricate Role of CXCR 4 in Cancer , 2015 .

[28]  J. Rickus,et al.  Extracellular Matrix Properties Regulate the Migratory Response of Glioblastoma Stem Cells in Three-Dimensional Culture. , 2015, Tissue engineering. Part A.

[29]  Tyler E. Miller,et al.  Brain tumor stem cells: Molecular characteristics and their impact on therapy. , 2014, Molecular aspects of medicine.

[30]  M. Chatterjee,et al.  Platelet‐derived CXCL12 (SDF‐1α): basic mechanisms and clinical implications , 2013, Journal of thrombosis and haemostasis : JTH.

[31]  Zhongmei Zhou,et al.  Krüppel-like Factor 5 Transcription Factor Promotes Microsomal Prostaglandin E2 Synthase 1 Gene Transcription in Breast Cancer* , 2013, The Journal of Biological Chemistry.

[32]  R. McLendon,et al.  Glioblastoma Stem Cells Generate Vascular Pericytes to Support Vessel Function and Tumor Growth , 2013, Cell.

[33]  A. Scorilas,et al.  Expression of Bcl2L12 in chronic lymphocytic leukemia patients: association with clinical and molecular prognostic markers , 2013, Medical Oncology.

[34]  Joseph Mainzer,et al.  FOR THE EXPRESSION , 2013 .

[35]  J. Weis,et al.  Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines , 2012, Journal of Neuro-Oncology.

[36]  Ryuya Yamanaka,et al.  Editorial: Brain tumor. Current status of treatment and its complications. , 1975 .

[37]  Shi-ting Li,et al.  CXCR4-positive subset of glioma is enriched for cancer stem cells. , 2011, Oncology research.

[38]  Bin Wang,et al.  The chemokine CXCL12 and its receptor CXCR4 promote glioma stem cell‐mediated VEGF production and tumour angiogenesis via PI3K/AKT signalling , 2011, The Journal of pathology.

[39]  M. Westphal,et al.  A distinct subset of glioma cell lines with stem cell‐like properties reflects the transcriptional phenotype of glioblastomas and overexpresses CXCR4 as therapeutic target , 2011, Glia.

[40]  C. Baldari,et al.  The CXCL12/CXCR4 axis as a therapeutic target in cancer and HIV-1 infection. , 2011, Current medicinal chemistry.

[41]  T. Wakabayashi,et al.  Glioma-initiating cells and molecular pathology: implications for therapy , 2011, Brain Tumor Pathology.

[42]  M. Weller,et al.  Glioblastoma stem cells , 2011, Cell and Tissue Research.

[43]  N. Karin.  The multiple faces of CXCL12 (SDF‐1α) in the regulation of immunity during health and disease , 2010, Journal of leukocyte biology.

[44]  B. Teicher,et al.  Molecular Pathways Clinical Cancer Research CXCL 12 ( SDF-1 ) / CXCR 4 Pathway in Cancer , 2010 .

[45]  Qianben Wang,et al.  Induction of Kruppel-like factor 5 expression by androgens results in increased CXCR4-dependent migration of prostate cancer cells in vitro. , 2009, Molecular endocrinology.

[46]  R. Thompson,et al.  Preferential expression of chemokine receptor CXCR4 by highly malignant human gliomas and its association with poor patient survival. , 2008, Neurosurgery.

[47]  Kathryn M. McMillan,et al.  CXCR4 EXPRESSION IS ELEVATED IN GLIOBLASTOMA MULTIFORME AND CORRELATES WITH AN INCREASE IN INTENSITY AND EXTENT OF PERITUMORAL T2‐WEIGHTED MAGNETIC RESONANCE IMAGING SIGNAL ABNORMALITIES , 2008, Neurosurgery.

[48]  L. Chin,et al.  Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma , 2008, Proceedings of the National Academy of Sciences.

[49]  C. Heeschen,et al.  Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. , 2007, Cell stem cell.

[50]  L. Chin,et al.  Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma. , 2007, Genes & development.

[51]  Ugo Orfanelli,et al.  Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma , 2004, Cancer Research.