c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1) attenuates curcumin-induced cell death differently from its family member, JNK-associated leucine zipper protein (JLP).

Curcumin, a major component of turmeric, is known to exhibit multiple biological functions including antitumor activity. We previously reported that the mitogen-activated protein kinase (MAPK) scaffold protein c-Jun NH2-terminal kinase (JNK)-associated leucine zipper protein (JLP) reduces curcumin-induced cell death by modulating p38 MAPK and autophagy through the regulation of lysosome positioning. In this study, we investigated the role of JNK/stress-activated protein kinase-associated protein 1 (JSAP1), a JLP family member, in curcumin-induced stress, and found that JSAP1 also attenuates curcumin-induced cell death. However, JSAP1 knockout showed no or little effect on the activation of JNK and p38 MAPKs in response to curcumin. In addition, small molecule inhibitors of JNK and p38 MAPKs did not increase curcumin-induced cell death. Furthermore, JSAP1 depletion did not impair lysosome positioning and autophagosome-lysosome fusion. Instead, we noticed substantial autolysosome accumulation accompanied by an inefficient autophagic flux in JSAP1 knockout cells. Taken together, these results indicate that JSAP1 is involved in curcumin-induced cell death differently from JLP, and may suggest that JSAP1 plays a role in autophagosome degradation and its dysfunction results in enhanced cell death. The findings of this study may contribute to the development of novel therapeutic approaches using curcumin for cancer.

JLP-JNK signaling protects cancer cells from reactive oxygen species-induced cell death.

Oxidative stress, which can be caused by an overproduction of reactive oxygen species (ROS), often leads to cell death. In recent years, c-Jun NH2-terminal kinase (JNK)-associated leucine zipper protein (JLP, also known as SPAG9 or JIP4), a scaffold protein for JNK mitogen-activated protein kinase (MAPK) signaling pathways, was found to serve as a novel biomarker for cancer. However, although JNK MAPK pathways are reported to be activated in response to various stimuli, including oxidative stress, whether JLP is involved in ROS signaling remains unknown. In this study, we examined the role of JLP in hydrogen peroxide (H2O2)-induced cancer cell death, and found that JLP knockdown (KD) cells exhibit a substantially enhanced cell death response, along with increased intracellular ROS levels. This is the first demonstration of a protective role for JLP in response to cell-death stimulation. We also found that the H2O2-induced JNK activation was attenuated in JLP KD cancer cells. The decreases in cell viability and JNK activation in the JLP KD cells were almost completely reversed by expressing wild-type JLP, but not a mutant JLP lacking the JNK-binding domain. These data collectively suggest that the JLP-JNK signaling pathway counteracts ROS-induced cancer cell death.