HuR-targeted nanotherapy in combination with AMD3100 suppresses CXCR4 expression, cell growth, migration and invasion in lung cancer.
The CXCR4 chemokine receptor has an important role in cancer cell metastasis. The CXCR4 antagonist, AMD3100, has limited efficacy in controlling metastasis. HuR, an RNA-binding protein, regulates CXCR4 in cancer cells. We therefore investigated whether targeting HuR using a siRNA-based nanoparticle plus AMD3100 would suppress CXCR4 and inhibit lung cancer metastasis. We treated human H1299 lung cancer cells with HuR-specific siRNA contained in a folate-targeted lipid nanoparticle (HuR-FNP) plus AMD3100, and compared this with AMD3100 alone, HuR-FNP alone and no treatment. HuR-FNP plus AMD3100 treatment produced a G1 phase cell cycle arrest and reduced cell viability above and beyond the effects of AMD3100 alone. HuR and CXCR4 mRNA and protein expression levels were markedly reduced in all treatment groups. Phosphorylated (p) AKT(S473) protein was also reduced. P27 protein expression increased with HuR-FNP and combination treatment. Promoter-based reporter studies showed that the combination inhibited CXCR4 promoter activity more than did either treatment alone. Cell migration and invasion was significantly reduced with all treatments; the combination provided the most inhibition. Reduced matrix metalloprotease (MMP)-2 and -9 expression was associated with reduced invasion in all treatment groups. Thus, we found that combined HuR and CXCR4 targeting effectively controlled lung cancer metastasis.
Department of Pathology, Stanton L. Young Biomedical Research Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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Muralidharan
Department of Pathology, Stanton L. Young Biomedical Research Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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Panneerselvam
Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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Chen
Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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Zhao
Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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Munshi
Department of Pathology, Stanton L. Young Biomedical Research Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|Graduate Program in Biomedical Sciences, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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Ramesh
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001596:Benzylamines; D002465:Cell Movement; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D000080027:Cyclams; D015536:Down-Regulation; D000067780:ELAV-Like Protein 1 / Q000037:antagonists & inhibitors*; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D053758:Nanoparticles / Q000378:metabolism / Q000627:therapeutic use*; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D006571:Heterocyclic Compounds; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; C088327:plerixafor