Cell death via DR5, but not DR4, is regulated by p53 in myeloma cells
Menée sur des lignées cellulaires de myélome multiple à l'aide d'anticorps monoclonaux (mapatumumab et lexatumumab), cette étude identifie un mécanisme de régulation de la mort cellulaire impliquant le récepteur DR5 et le gène p53
Myeloma cells are sensitive to TRAIL through both receptors, DR4 and DR5. Because p53 directly modulates expression of death receptors, we wondered whether p53 could modulate myeloma sensitivity to TRAIL. By using DR4 and DR5 agonistic human mAbs, respectively mapatumumab and lexatumumab, we show that TP53Wt HMCLs (n=9) but not TP53Abn HMCLs (n=22) were killed by lexatumumab (p<0.01) while TP53Abn HMCLs but not TP53Wt HMCLs were killed by mapatumumab (p<0.01). Compared with TP53Abn HMCLs, TP53Wt HMCLs overexpressed DR5 in correlation with sensitivity to lexatumumab. Both non-genotoxic (nutlin3a) and genotoxic (melphalan) p53 inducing stresses increased DR5 expression only in TP53Wt HMCLs and synergistically increased lexatumumab efficiency. In contrast, nutlin3a or melphalan neither increased DR4 expression nor sensitivity of TP53Wt or TP53Abn HMCLs to mapatumumab. Conversely, silencing of p53 in TP53Wt NCI-H929 strongly decreased DR5 expression and induced resistance to nutlin3a and lexatumumab but did not modulate DR4 expression or sensitivity to mapatumumab. Chromatin immunoprecipation and DISC immunoprecipitation assays respectively showed that increase of lexatumumab efficiency induced by nutlin3a was related to a p53 dependent increase of DR5 expression and to the amount of activated caspase 8 within the DISC upon DR5 triggering. In primary myeloma cells without del17p, nutlin3a increased DR5 expression and lexatumumab efficiency but did not increase mapatumumab efficiency. These data show that sensitivity of myeloma via DR5, but not via DR4, is controlled by p53 and provide a framework for DR5 therapy in patients with multiple myeloma without del17p.
Cancer Research 2012