TAK1 inhibitor 5Z-7-oxozeaenol sensitizes cervical cancer to doxorubicin-induced apoptosis

Abstract

Aberrant activation of nuclear factor-κB (NF-κB) allows cancer cells to escape chemotherapy-induced cell death and acts as one of the major mechanisms of acquired chemoresistance in cervical cancer. TAK1, a crucial mediator that upregulates NF-κB activation in response to cellular genotoxic stress, is required for tumor cell viability and survival. Herein, we examined whether TAK1 inhibition is a potential therapeutic strategy for treating cervical cancer. We found that TAK1 inhibitor 5Z-7-oxozeaenol significantly augmented the cytotoxic effects of Dox in a panel of cervical cancer cell lines. Treatment with 5Z-7-oxozeaenol hindered Dox-induced NF-κB activation and promoted Dox-induced apoptosis in cervical cancer cells. Moreover, 5Z-7-oxozeaenol showed similar effects in both positive and negative human papillomavirus-infected cervical cancer cells. Taken together, our results provide evidence that TAK1 inhibition significantly sensitizes cervical cancer cells to chemotherapy-induced cell death and supports the use of TAK1 inhibitor with current chemotherapies in the clinic for patients with refractory cervical cancer.

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation

“…The cells were then separated and treated with 0.5 µM of one of the following: 5Z‐7‐oxozeaenol (OZ) (Sigma, St. Louis, MO), 5Z‐zeaenol (5Z) (CALBIOCHEM), or AZ‐TAK1 (3‐[(aminocarbonyl)amino]‐5‐[4‐(4‐morpholinylmethyl)phenyl]‐2‐thiophenecarboxamide) (Toronto Research Chemicals, Toronto, Canada), and incubated for 40–60 min. This concentration was selected based on successful TAK1 inhibition by OZ in various of cell types and models 30‐33 and no impact on cell viability was detectable. The groups were then stimulated with 10 or 100 ng/ml TNP‐BSA (Biosearch Technologies, Novato, CA) and/or 100 ng/ml SCF (Peprotech, Dollard des Ormeaux, QC).…”

“…29 BMMC cultures were maintained at 37 • C and 5% CO 2 as previously described. 16 This concentration was selected based on successful TAK1 inhibition by OZ in various of cell types and models [30][31][32][33] and no impact on cell viability was detectable. The groups were then stimulated with 10 or 100 ng/ml TNP-BSA (Biosearch Technologies, Novato, CA) and/or 100 ng/ml SCF (Peprotech, Dollard des Ormeaux, QC).…”

Paclitaxel induces apoptosis through the TAK1–JNK activation pathway

“…Several research teams have reported that PTX-induced apoptosis is associated with p38 [8][9][10], JNK [7,8,12,13], ERK [8] and NF-jB [11], and TAK1 is a key kinase in these signal transduction pathways [15][16][17][18][20][21][22]. PTX mediated dose-and time-dependent induction of apoptosis and an increase in endogenous TAK1 and TAB1 levels.…”

“…TAB1 (TAK1-binding protein 1) is a TAK1binding protein [17,18]. TAK1 and TAB1 play an important role in cell apoptosis through the p38 [19,20], ERK [2], NF-jB [21,22] and JNK [19,23,24] signal transduction pathways.…”

TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation

“…TAK1 is important for lysosomal rupture–induced inflammasome activation ( Okada et al, 2014 ) and hypotonic stimulation (altering cellular volume–induced inflammasome activation; Compan et al, 2012 ). Currently, there is a tremendous interest in TAK1 inhibition as a therapeutic application for inflammatory disease management and cancer immunotherapy ( Sakurai, 2012 ; Singh et al, 2012 ; Huang et al, 2015 ; Kilty and Jones, 2015 ; Guan et al, 2017 ). However, prolonged TAK1 inactivation also results in severe inflammation, bone disorders, and cancer development in mice and humans ( Shim et al, 2005 ; Omori et al, 2006 ; Kajino-Sakamoto et al, 2008 , 2010 ; Tang et al, 2008 ; Bettermann et al, 2010 ; Inokuchi et al, 2010 ; Lamothe et al, 2013 ; Le Goff et al, 2016 ; Wade et al, 2016 ).…”