Self-targeted knockdown of CD44 improves cisplatin sensitivity of chemoresistant non-small cell lung cancer cells
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Chemoresistance remains a major challenge for effective chemotherapy of non-small-cell lung carcinoma (NSCLC). CD44 expression is related to the susceptibility of various cancer cell types to anticancer drugs. Here, we systematically investigated the CD44-dependent chemoresistance of NSCLC cells and developed a liposomal siRNA delivery system to overcome this chemoresistance by the self-targeted downregulation of CD44.
We confirmed the relationship between the expression of CD44 and the chemosensitivity of NSCLC cells using flow cytometry and MTT assay. We then generated and characterized cisplatin-resistant cell lines and compared the expression of CD44 in resistant cells to that in parental cells using western blotting. To evaluate whether the chemosensitivity of resistant cells depends on CD44 expression, we performed CD44 knockdown using CD44 siRNA and detected the chemosensitivity of these cells. Additionally, we prepared hyaluronic acid (HA)-coated liposomes as a targeted delivery system to selectively deliver CD44-specific siRNA to chemoresistant NSCLC cells and observed whether the chemosensitivity of these cells was improved.
We found that CD44 expression is inversely proportional to the degree of cellular response to cisplatin chemotherapy and that CD44 is overexpressed in chemoresistant NSCLC cells. By performing CD44 knockdown using siRNA, we reconfirmed that the chemosensitivity of resistant cells depends on CD44 expression. We also observed that HA-liposome-mediated siRNA delivery prior to cisplatin chemotherapy significantly reduced CD44 expression and enhanced cisplatin sensitivity in chemoresistant NSCLC cells.
These results suggest that self-targeted downregulation of chemoresistance-associated cell surface proteins during chemotherapy is an effective therapeutic strategy for overcoming the chemoresistance of NSCLC cells.
KeywordsChemoresistance Non-small cell lung carcinoma Hyaluronic acid-coated liposomes
Non-small cell lung cancer
Cancer stem cell
BCL2-associated X apoptosis regulator
Multidrug resistance-associated protein 2
Conception and design: YHQ, J-HP, and HKK. Development of methodology: YHQ. Acquisition of data (provided materials, provided facilities, etc.): YHn, JL, and YHC. Analysis and interpretation of data (e.g. statistical analysis, biostatistics, computational analysis): YHQ. Writing, review, and/or revision of the manuscript: YHQ, J-HP, and HKK. Administrative, technical, or material support (i.e. reporting or organizing data, constructing databases): JL, YC, and YHC. Study supervision: J-HP and HKK.
This work was supported by a Korea University Grant and the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science, and Technology (NRF-2017R1E1A1A01074847) and Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (Grant no. HI17C0654).
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Conflict of interest
All authors read and approved the final version of the manuscript, and the authors declare no conflicts of interest.
- 30.Bourguignon LY, Spevak CC, Wong G, Xia W, Gilad E (2009) Hyaluronan-CD44 interaction with protein kinase Cϵ promotes oncogenic signaling by the stem cell marker Nanog and the production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J Biol Chem 284:26533–26546CrossRefPubMedPubMedCentralGoogle Scholar