ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells

BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling

“…As knockdown of ZAK alone can account for up to 93.7% of the effect of PLX4720 treatment, we conclude that the potent inhibition of JNK activation and resultant apoptosis by PLX4720 and vemurafenib is due to the off-target inhibition of ZAK principally, with smaller additional contributions from inhibition of MKK4 and MAP4K5, which abrogates the activation of the two kinases essential for JNK phosphorylation and activation: MKK4 and MKK7 (Figures 2H–I,3D–E, Figure 3—figure supplement 4). Consistent with our findings, ZAK has been shown to be critically important for JNK activation upstream of MKK4 and MKK7 (Wang et al, 2005) and doxorubicin-induced apoptosis (Sauter et al, 2010; Wong et al, 2013). …”

“…Our results have also shown that there are significant differences between the BRAFi vemurafenib and dabrafenib (Figure 6—figure supplements 2,3) with respect to these off-target effects in cells (even though their relative selectivities for BRAF over ZAK are similar) and this may, in part, explain why they differ in rates of cSCC (Flaherty et al, 2010; Chapman et al, 2011; Falchook et al, 2012; Hauschild et al, 2012; Long et al, 2012; Sosman et al, 2012). At present it is unclear why ZAK appears to be a common off-target kinase and whether structural similarities with other kinases may explain this (Sauter et al, 2010; Wong et al, 2013). …”

Sorafenib Suppresses JNK-Dependent Apoptosis through Inhibition of ZAK

“…ZAK is critically important for JNK activation upstream of MKK4 and MKK7(28) and is important for doxorubicin-induced apoptosis(29, 30). TAOK2 has been implicated to be an activator of JNK as well(31–35).…”

Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome

“…34 Prior studies had demonstrated that doxorubicin is an inhibitor of protein synthesis. 35,36 To determine if doxorubicin and daunorubicin would inhibit protein synthesis at the concentrations employed in the current studies, we exposed unprimed and LPS-primed BMDM to doxorubicin (10 μM) or daunorubicin (1 μM) for 4 or 8 h, at which time cells were exposed to [ 3 H]-leucine for 30 min. Exposure of unprimed and LPS-primed cells to doxorubicin or daunorubicin resulted in a progressive decrease in the incorporation of [ 3 H]-leucine, resulting in 85-90% decrease by 8 h (Fig.…”

“…39,41 Doxorubicin and daunorubicin exhibit the two salient characteristics of ribotoxic stress agents: the inhibition of protein synthesis and the ZAK-mediated activation of JNK and p38. 36 Nigericin and valinomycin are potassium ionophores that activate the NLRP3 inflammasome 33,42 and are also potent inhibitors of protein synthesis. [43][44][45] We have determined that a broad range of protein synthesis inhibitors lead to activation of the NLRP3 inflammasome in BMDMs in vitro (unpublished).…”