Enhanced invasiveness of drug-resistant acute myeloid leukemia cells through increased expression of matrix metalloproteinase-2.
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.
Song
Ju Han
JH
Korea University, Seoul, Republic of Korea.
Kim
Seung Hyun
SH
Cho
Daeho
D
Lee
Il-Kwon
IK
Kim
Hyeoung-Joon
HJ
Kim
Tae Sung
TS
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001578:Benzopyrans / Q000494:pharmacology; D001752:Blast Crisis; D015153:Blotting, Western; D003561:Cytarabine / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D055815:Young Adult
C483331:1',3-dihydro-1'-(2-carboxyethyl)-3,3-dimethyl-6-nitrospiro-(2H-1-benzopyran-2,2'-(2H)-indoline); D001578:Benzopyrans; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D003561:Cytarabine; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2; D015255:Idarubicin