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Published on: March 17, 2020
HuR-targeted nanotherapy in combination with AMD3100 suppresses CXCR4 expression, cell growth, migration and invasion
R Muralidharan1,2, J Panneerselvam1,2, A Chen3
1Department of Pathology, Stanton L. Young Biomedical Research Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Abstract:
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.
Insights
Targeting HuR (human antigen R) and CXCR4 with a novel nanoparticle delivery system effectively suppressed lung cancer metastasis. This combination therapy reduced cell viability and invasion more than AMD3100 alone.
Area of Science:
- Oncology
- Molecular Biology
- Nanotechnology
Background:
- The CXCR4 chemokine receptor plays a critical role in cancer cell metastasis.
- Current CXCR4 antagonists like AMD3100 have limited efficacy in controlling metastasis.
- HuR (human antigen R), an RNA-binding protein, is a key regulator of CXCR4 in cancer cells.
Purpose of the Study:
- To investigate the efficacy of targeting HuR with a siRNA-based nanoparticle combined with AMD3100 to suppress CXCR4 and inhibit lung cancer metastasis.
Main Methods:
- Human H1299 lung cancer cells were treated with HuR-specific siRNA encapsulated in a folate-targeted lipid nanoparticle (HuR-FNP) plus AMD3100.
- Comparative analysis included AMD3100 alone, HuR-FNP alone, and no treatment.
- Assessed cell cycle, viability, gene/protein expression (HuR, CXCR4, pAKT, p27, MMP-2, MMP-9), promoter activity, cell migration, and invasion.
Main Results:
- Combined HuR-FNP and AMD3100 treatment induced G1 phase cell cycle arrest and reduced cell viability more effectively than AMD3100 alone.
- Significant reductions in HuR and CXCR4 mRNA and protein levels were observed across all treatment groups.
- The combination therapy markedly reduced cell migration, invasion, and matrix metalloprotease (MMP)-2 and -9 expression, outperforming monotherapies.
Conclusions:
- Combined targeting of HuR and CXCR4 using HuR-FNP and AMD3100 represents a promising strategy for effectively controlling lung cancer metastasis.
- This approach offers enhanced inhibition of metastasis compared to targeting CXCR4 alone.
