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Enhanced invasiveness of drug‐resistant acute myeloid leukemia cells through increased expression of matrix metalloproteinase‐2
Author(s) -
Song Ju Han,
Kim Seung Hyun,
Cho Daeho,
Lee IlKwon,
Kim HyeoungJoon,
Kim Tae Sung
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24386
Subject(s) - myeloid leukemia , leukemia , cancer research , matrix metalloproteinase , bone marrow , cytarabine , drug resistance , myeloid , downregulation and upregulation , biology , immunology , medicine , biochemistry , gene , microbiology and biotechnology
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. © 2009 UICC