T-cell receptor (TCR) signaling-induced activation of NF-κB requires assembly of the CARD11-BCL10-MALT-1 complex and IκB kinase (IKK). Gain-of-function alterations in this component of the TCR/NF-κB pathway are associated with the development of HTLV-1-driven adult T-cell leukemia (ATL). We aimed to determine if inhibition of MALT-1-mediated NF-κB activation could have anti-ATL activity.
RT-PCR, immunoblotting and electrophoretic mobility shift assays were performed to assess expression levels of MALT-1 and the intracellular signaling cascades. Cell proliferation, cell cycle progression and apoptotic events were examined using WST-8 assays, flow cytometry and Hoechst 33342 staining.
MALT-1 expression was upregulated in ATL-derived T-cell lines compared to that in normal PBMCs and uninfected or HTLV-1-transformed T-cell lines. Targeting MALT-1 with siRNA decreased cell proliferation. A MALT-1 inhibitor (MI-2) suppressed cleavage of the MALT-1-target protein, CYLD and inhibited proliferation via G1 phase arrest. MI-2 induced apoptosis through caspase-3/8/9 activation and inhibited the phosphorylation of IKKα/β and IκBα, resulting in the accumulation of IκBα and suppression of NF-κB-DNA binding. Additionally, MI-2 inhibited the expression of apoptosis- and cell cycle-related proteins regulated by NF-κB.
MALT-1 plays an important regulatory role in NF-κB signaling during ATL-genesis, and targeting MALT-1 is a promising therapeutic strategy for this disease.
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