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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 3/2019

01-03-2019 | Original Article

Self-targeted knockdown of CD44 improves cisplatin sensitivity of chemoresistant non-small cell lung cancer cells

Authors: Yu Hua Quan, Ji-Young Lim, Byeong Hyeon Choi, Yeonho Choi, Young Ho Choi, Ji-Ho Park, Hyun Koo Kim

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2019

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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.
Appendix
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Literature
1.
2.
Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234CrossRefPubMed
3.
4.
Kachalaki S, Ebrahimi M, Khosroshahi LM, Mohammadinejad S, Baradaran B (2016) Cancer chemoresistance; biochemical and molecular aspects: a brief overview. Eur J Pharm Sci 89:20–30CrossRefPubMed
5.
6.
7.
Dragu DL, Necula LG, Bleotu C, Diaconu CC, Chivu-Economescu M (2015) Therapies targeting cancer stem cells: Current trends and future challenges. World J Stem Cells 7:1185PubMedPubMedCentral
8.
Eramo A, Haas T, De Maria R (2010) Lung cancer stem cells: tools and targets to fight lung cancer. Oncogene 29:4625–4635CrossRefPubMed
9.
Pham PV, Phan NL, Nguyen NT et al (2011) Differentiation of breast cancer stem cells by knockdown of CD44: promising differentiation therapy. J Transl Med 9:209CrossRefPubMedPubMedCentral
10.
Zhao S, Chen C, Chang K et al (2016) CD44 expression level and isoform contributes to pancreatic cancer cell plasticity, invasiveness, and response to therapy. Clin Cancer Res 22:5592–5604CrossRefPubMedPubMedCentral
11.
Zhang S, Balch C, Chan MW et al (2008) Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res 68:4311–4320CrossRefPubMedPubMedCentral
12.
Hiscox S, Baruha B, Smith C et al (2012) Overexpression of CD44 accompanies acquired tamoxifen resistance in MCF7 cells and augments their sensitivity to the stromal factors, heregulin and hyaluronan. BMC Cancer 12:458CrossRefPubMedPubMedCentral
13.
Dick D (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:1CrossRef
14.
Hong SP, Wen J, Bang S, Park S, Song SY (2009) CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells. Int J Cancer 125:2323–2331CrossRefPubMed
15.
Boulbes DR, Chauhan GB, Jin Q, Bartholomeusz C, Esteva FJ (2015) CD44 expression contributes to trastuzumab resistance in HER2-positive breast cancer cells. Breast Cancer Res Treat 151:501–513CrossRefPubMed
16.
Bjorklund CC, Baladandayuthapani V, Lin HY et al (2014) Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: therapeutic implications. Leukemia 28:373–383CrossRefPubMed
17.
Roudi R, Madjd Z, Ebrahimi M, Samani F, Samadikuchaksaraei A (2014) CD44 and CD24 cannot act as cancer stem cell markers in human lung adenocarcinoma cell line A549. Cell Mol Biol Lett 19:23–36CrossRefPubMed
18.
Sung WJ, Park K-S, Kwak SG, Hyun D-S, Jang JS, Park K-K (2015) Epithelial-mesenchymal transition in patients of pulmonary adenocarcinoma: correlation with cancer stem cell markers and prognosis. Int J Clin Exp Pathol 8:8997PubMedPubMedCentral
19.
d’Amato TA, Landreneau RJ, McKenna RJ, Santos RS, Parker RJ (2006) Prevalence of in vitro extreme chemotherapy resistance in resected nonsmall-cell lung cancer. Ann Thorac Surg 81:440–447CrossRefPubMed
20.
Katayama R, Shaw AT, Khan TM et al (2012) Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 4:120ra117–120ra117CrossRef
21.
Pao W, Miller VA, Politi KA et al (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73CrossRefPubMedPubMedCentral
22.
Luo Y, Prestwich GD (1999) Synthesis and selective cytotoxicity of a hyaluronic acid-antitumor bioconjugate. Bioconj Chem 10:755–763CrossRef
23.
Toole BP, Ghatak S, Misra S (2008) Hyaluronan oligosaccharides as a potential anticancer therapeutic. Curr Pharm Biotechnol 9:249–252CrossRefPubMed
24.
Toole BP, Slomiany MG (2008) Hyaluronan, CD44 and Emmprin: partners in cancer cell chemoresistance. Drug Resist Updates 11:110–121CrossRef
25.
Quan YH, Kim B, Park JH, Choi Y, Choi YH, Kim HK (2014) Highly sensitive and selective anticancer effect by conjugated HA-cisplatin in non-small cell lung cancer overexpressed with CD44. Exp Lung Res 40:475–484CrossRefPubMed
26.
Leung EL-H, Fiscus RR, Tung JW et al (2010) Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS One 5:e14062CrossRefPubMedPubMedCentral
27.
Ohashi R, Takahashi F, Cui R et al (2007) Interaction between CD44 and hyaluronate induces chemoresistance in non-small cell lung cancer cell. Cancer Lett 252:225–234CrossRefPubMed
28.
Shi Y, Liu C, Liu X, Tang DG, Wang J (2014) The microRNA miR-34a inhibits non-small cell lung cancer (NSCLC) growth and the CD44 hi stem-like NSCLC cells. PLoS One 9:e90022CrossRefPubMedPubMedCentral
29.
Galluzzi L, Senovilla L, Vitale I et al (2012) Molecular mechanisms of cisplatin resistance. Oncogene 31:1869–1883CrossRefPubMed
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 284:26533–26546CrossRefPubMedPubMedCentral
Metadata
Title
Self-targeted knockdown of CD44 improves cisplatin sensitivity of chemoresistant non-small cell lung cancer cells
Authors
Yu Hua Quan
Ji-Young Lim
Byeong Hyeon Choi
Yeonho Choi
Young Ho Choi
Ji-Ho Park
Hyun Koo Kim
Publication date
01-03-2019
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 3/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-018-3737-y

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