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

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. ' 2009 UICC

Influence of stress on extracellular matrix and integrin biology

“…This could explain the loss of heart collagen mass in doxorubicintreated animals, one of the features of anthracyclininduced cardiotoxicity. In agreement with this observation, MMP overproduction has been also described in multidrug-resistant (MDR1) tumor cells (Song et al, 2009).…”

Potentiation of Anticancer Drugs: Effects of Pentoxifylline on Neoplastic Cells

“…A close association between the expression or activity of distinct matrix metalloproteinases and both tumor cell invasion and metastasis has been described [28]. Resistance of AML cells to anticancer drugs was described to be associated with increased activity and expression of MMP-2, which induced an enhancement in their invasivity [29]. This resistance of AML cells to anticancer drugs was also found to lead to a lack of drug-induced cell death, such as apoptosis.…”

MicroRNA-21 induces resistance to the anti-tumour effect of interferon-α/5-fluorouracil in hepatocellular carcinoma cells

“…Other studies reported miR-21-induced chemoresistance by downregulation of PDCD4 proteins, on the basis of previous reports of the relation between PDCD4 and chemosensitivity (Jansen et al , 2004; Bourguignon et al , 2009). Moriyama et al (2009) also reported miR-21 induced chemoresistance to gemcitabine and changes in MMPs expression, and speculated that these miR-21-induced changes in chemoresistance were mediated through MMPs, based on previous reports that the miR-21 indirectly induced MMPs expression (by negative regulation of tissue inhibitor of metalloproteinases 3 (TIMP3) and reversion-inducing cysteine-rich protein with Kazal motifs (RECK)) and that MMPs levels correlated significantly with chemosensitivity (Gabriely et al , 2008; Almendro et al , 2009; Song et al , 2009). On the other hand, in addition to the confirmation of miR-21-induced chemoresistance and changes in the aforementioned target molecules in pre-miR-21-transfected cells including PTEN, PDCD4, and MMPs, we also demonstrated that the miR-21-induced changes in chemoresponse were ameliorated by downregulation of PTEN or PDCD4 by the respective siRNA.…”