Paclitaxel induces apoptosis through the TAK1-JNK activation pathway.

Paclitaxel (PTX) has previously been used to treat tumours of various tissue origins, such as lung, breast, ovarian, prostate cancer, and leukemia. PTX-induced apoptosis is associated with p38 MAPK, ERK, NF-κB and JNK/ SAPK pathway. TAK1 and TAB1 play an important role in cell apoptosis through the P38, ERK, NF-κB and JNK signal transduction pathways. To investigate the role of TAK1 in PTX-induced cell apoptosis, we treated HEK293 and 8305C cells with 0-20 µM PTX for 6, 12 or 24 h. To investigate whether TAK1 can cooperate with PTX for cancer treatment, we transfected cells with TAK1, TAB1 or control plasmid and treated with PTX (3-10 µM) for 9-24 h. Apoptosis rates were analysed by flow cytometry (annexin V+). Endogenous TAK1 and TAB1, caspase 7 cleavage, PARP cleavage, Bcl-xL level, phospho-P44/42, phospho-JNK, and phospho-P38 were detected by western blot. We show that in HEK293 and 8305C cells, PTX enhanced the endogenous TAK1/TAB1 level and induced cells apoptosis in a dose- and time-dependent manner. Upon TAK1 overexpression in HEK293 cells treated with PTX, apoptosis rate, JNK phosphorylation and PARP cleavage increased contrary to heat-shocked or untreated cells. CRISPR-editing of the tak1 gene upon PTX treatment resulted in lower phospho-JNK and PARP cleavage levels than in cells transfected with the control or the TAK1- or TAB1 + TAK1-containing plasmids. TAK1-K63A could not induce JNK phosphorylation or PARP cleavage. We conclude that PTX induces HEK293 and 8305C cell apoptosis through the TAK1-JNK activation pathway, potentially highlighting TAK1's role in chemosensitivity.