Yu Hua Quan1,2, Ji-Young Lim3, Byeong Hyeon Choi1,2, Yeonho Choi4, Young Ho Choi1, Ji-Ho Park5, Hyun Koo Kim6,7. 1. Department of Thoracic and Cardiovascular Surgery, Korea University Guro Hospital, College of Medicine, Korea University, 148, Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea. 2. Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 02841, Republic of Korea. 3. Department of Bio and Brain Engineering and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea. 4. Department of Bio-Convergence, Korea University, Seoul, 02841, Republic of Korea. 5. Department of Bio and Brain Engineering and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea. jihopark@kaist.ac.kr. 6. Department of Thoracic and Cardiovascular Surgery, Korea University Guro Hospital, College of Medicine, Korea University, 148, Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea. kimhyunkoo@korea.ac.kr. 7. Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 02841, Republic of Korea. kimhyunkoo@korea.ac.kr.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.