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MAPK p38 and JNK have opposing activities on TRAIL-induced apoptosis activation in NSCLC H460 cells that involves RIP1 and caspase-8 and is mediated by Mcl-1

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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce both caspase-dependent apoptosis and kinase activation in tumor cells. Here, we examined the consequences and mechanisms of TRAIL-induced MAPKs p38 and JNK in non-small cell lung cancer (NSCLC) cells. In apoptosis sensitive H460 cells, these kinases were phosphorylated, but not in resistant A549 cells. Time course experiments in H460 cells showed that induction of p38 phosphorylation preceded that of JNK. To explore the function of these kinases in apoptosis activation by TRAIL, chemical inhibitors or siRNAs were employed to impair JNK or p38 functioning. JNK activation counteracted TRAIL-induced apoptosis whereas activation of p38 stimulated apoptosis. Notably, the serine/threonine kinase RIP1 was cleaved following TRAIL treatment, concomitant with detectable JNK phosphorylation. Further examination of the role of RIP1 by short hairpin (sh)RNA-dependent knockdown or inhibition by necrostatin-1 showed that p38 can be phosphorylated in both RIP1-dependent and -independent manner, whereas JNK phosphorylation occurred independent of RIP1. On the other hand JNK appeared to suppress RIP1 cleavage via an unknown mechanism. In addition, only the activation of JNK by TRAIL was caspase-8-dependent. Finally, we identified Mcl-1, a known substrate for p38 and JNK, as a downstream modulator of JNK or p38 activity. Collectively, our data suggest in a subset of NSCLC cells a model in which TRAIL-induced activation of p38 and JNK have counteracting effects on Mcl-1 expression leading to pro- or anti-apoptotic effects, respectively. Strategies aiming to stimulate p38 and inhibit JNK may have benefit for TRAIL-based therapies in NSCLC.

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Acknowledgments

This research was performed within the framework of project T3-112 of the Dutch Top Institute Pharma and supported by grant RUG2011-5211 from the Dutch Cancer Society. We thank Dr. S. Cillesen for technical assistance.

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Authors and Affiliations

  1. Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands

    Kaamar Azijli, Saravanan Yuvaraj, Steven de Jong & Frank A. E. Kruyt

  2. Department of Pharmaceutical Biology, University of Groningen, Groningen, The Netherlands

    Ingrid van Roosmalen

  3. Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

    Kaamar Azijli, Koen Flach, Elisa Giovannetti & Godefridus J. Peters

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  1. Kaamar Azijli
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Correspondence to Frank A. E. Kruyt.

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Azijli, K., Yuvaraj, S., van Roosmalen, I. et al. MAPK p38 and JNK have opposing activities on TRAIL-induced apoptosis activation in NSCLC H460 cells that involves RIP1 and caspase-8 and is mediated by Mcl-1. Apoptosis 18, 851–860 (2013). https://doi.org/10.1007/s10495-013-0829-3

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