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

Han Song Ju, Hyun Kim Seung, Daeho Cho, Il Kwon Lee, Hyeoung Joon Kim, Sung Kim Tae

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1074-1081
Number of pages8
JournalInternational Journal of Cancer
Volume125
Issue number5
DOIs
Publication statusPublished - 2009 Sep 1

Keywords

  • Acute myeloid leukemia
  • Drug resistance
  • Invasion
  • Matrix metalloproteinase-2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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