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Enhanced invasiveness of drug-resistant acute myeloid leukemia cells through increased expression of matrix metalloproteinase-2

Authors
Song, Ju HanKim, Seung HyunCho, DaehoLee, Il-KwonKim, Hyeoung-JoonKim, Tae Sung
Issue Date
1-Sep-2009
Publisher
WILEY
Keywords
drug resistance; invasion; acute myeloid leukemia; matrix metalloproteinase-2
Citation
INTERNATIONAL JOURNAL OF CANCER, v.125, no.5, pp.1074 - 1081
Journal Title
INTERNATIONAL JOURNAL OF CANCER
Volume
125
Number
5
Start Page
1074
End Page
1081
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/13686
DOI
10.1002/ijc.24386
ISSN
0020-7136
Abstract
The acquired drug resistance as well as extramedullary tissue infiltration of leukemic cells is a major obstacle in leukemia treatment. Excessive egress of leukemia cell blasts results in invasion into various organs or tissues, which is facilitated by the catalytic activities of matrix metalloproteinases (MMPs). However, the migration of chemoresistant leukemia cells remains unclear. Here, we generated drug-resistant variants of the human acute myeloid leukemia cell line (AML-2/WT) by stepwise exposure to anticancer drugs and evaluated the level of MMP-2 in the drug-resistant variants, along with their invasiveness. Each of the drug-resistant cell variants demonstrated predominant increases in the expression and gelatinolytic activity of MMP-2 as well as in invasiveness, which were significantly suppressed by both a MMP-2 Inhibitor and a blocking antibody. Knockdown experiments using MMP-2 short hairpin RNA also indicated that its upregulation was strongly associated with the cells' increased invasive properties. Importantly, elevated levels of MMP-2 activity and invasiveness were observed in ex vivo mononuclear cell of bone marrow from patients with poor responses to chemotherapy. These findings suggest that advanced malignancy due to acquired drug resistance is responsible for the progressive invasiveness of leukemia cells via MMP-2. (C) 2009 UICC
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