TAK1 regulates NF-κB and mediates JNK-dependent apoptosis and chemosensitivity as well as p38-dependent invasion in MDA-MB-231 cells

Background and Objective: Triple-negative breast cancer (TNBC) represents the most lethal subtype of breast cancer due to its aggressive clinical features and with associated chemoresistance, which is lack of effective therapeutic targets.We examined the role of transforming growth factor-β-activated kinase 1 (TAK1) in TNBC MDA-MB-231 cells and explore the mechanism. Design and Methods: We utilized an TAK1-specific RNA interference (TAK1 siRNA) or TAK1-specific short hairpin RNA (TAK1 shRNA) to inhibit TAK1 expression or TAK1 overexpression by MYC-TAK1 transfection for evaluating its antitumor effect and chemosensitization as well as the invasive ability in MDA-MB-231 cells in vitro. Using the specific small molecule inhibitor or RNA interference, we assessed the molecular mechanisms of TAK1 underlying control of the functional role of MDA-MB-231 cells. In vivo, TAK1 shRNA-MDA-MB-231cells were subcutaneously injected or tail vein injection or treated with doxorubicin. Tumor volume and lung metastasis was assessed. Results: Depletion of TAK1 induces Bax-dependent apoptosis and enhanced the sensitivity of MDA-MB-231cells to doxorubicin or cisplatin in vitro. Depletion of TAK1 inhibited cell invasion in vitro by MMP-9,13-dependent way. Mechanistically, depletion of TAK1 inhibited NF-κB activity and promoted JNK phosphorylation, leading to Bax and cleaved-caspase-3 upregulation. JNK inhibitor SP600125 treatment decreased Bax expression and inhibited TAK1 depletion-induced apoptosis and chemosensitivity. p38 inhibitor SB 203580 treatment activated MMP-9,13 and re-established cell invasion. JNK1/2 and p38 was regulated by NF-κB, which was positively regulated by TAK1. Doxorubicin or cisplatin treatment activated NF-κB and reduced Bax expression, leading to decreased cell apoptosis. In vivo, targeting TAK1 inhibited lung metastasis and enhanced the chemosensitivity to doxorubicin. Conclusion: TAK1 regulates NF-κB and mediates JNK-Bax-dependent apoptosis and chemosensitivity as well as p38-MMPs-dependent invasion in MDA-MB-231 cells. Therefore, targeting TAK1 or targeting specific pathways using pharmacological compounds might be an important strategy for TNBC therapy.