Abstract
Aplidin™ is an antitumor drug that induces apoptosis and activates EGFR, Src, JNK and p38MAPK. Here, we show that Aplidin™ induces c-JUN, JUN B, JUN D, c-FOS, FRA-1 and FOS B genes of the activator-protein (AP)-1 family, and also p65/RELA, a major component of nuclear factor-kappa B (NF-κB). Concordantly, Aplidin™ increases AP-1 and NF-κB activity. c-FOS induction depends on EGFR, Src and JNK/p38MAPK. In contrast, induction of c-JUN does not require EGFR activity and p65/RELA induction is only partially dependent on these kinases. We used several genetically deficient cells to identify the critical target of Aplidin™. Mouse embryo fibroblasts (MEFs) deficient for src, yes and fyn, and those lacking all p38MAPK isoforms displayed normal Aplidin™ sensitivity (IC50=12 nM). In contrast, MEFs lacking jnk1 and jnk2, which do not express any JNK isoform, were much less sensitive (IC50>500 nM). Furthermore, cells lacking c-jun or expressing a c-Jun protein in which JNK targets Ser63/73 were mutated (c-JunAA) showed intermediate sensitivity (IC50=60 nM). Additionally, Aplidin™ has higher cytotoxic activity against proliferating than quiescent cells, which is reflected in higher JNK activation. We conclude that phosphorylation by JNK of c-Jun and additional substrate(s) is crucial for Aplidin™ activity.
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Acknowledgements
We thank those who appear in the section on Materials and methods for providing us with cells or antibodies and Robin Rycroft for his valuable assistance in the preparation of the English manuscript. This work was partly supported by Grant SAF01-2291 from Ministerio de Ciencia y Tecnología of Spain.
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Cuadrado, A., González, L., Suárez, Y. et al. JNK activation is critical for Aplidin™-induced apoptosis. Oncogene 23, 4673–4680 (2004). https://doi.org/10.1038/sj.onc.1207636
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DOI: https://doi.org/10.1038/sj.onc.1207636
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