Targeting Mcl-1 for multiple myeloma (MM) therapy: Drug-induced generation of Mcl-1 fragment Mcl-1128-350 triggers MM cell death via c-Jun upregulation

Fengjuan Fan, Giovanni Tonon, Muhammad Hasan Bashari, Sonia Vallet, Elena Antonini, Hartmut Goldschmidt, Henning Schulze-Bergkamen, Joseph T. Opferman, Martin Sattler, Kenneth C. Anderson, Dirk Jäger, Klaus Podar*

*Korrespondierende:r Autor:in für diese Arbeit

Publikation: Beitrag in Fachzeitschrift (peer-reviewed)Artikel in Fachzeitschrift

27 Zitate (Scopus)

Abstract

Myeloid cell leukemia-1 (Mcl-1, HGNC: 6943), a pro-survival member of the Bcl-2 family, plays a crucial role in Multiple Myeloma (MM) pathogenesis and drug resistance, thus representing a promising therapeutic target in MM. A novel strategy to inhibit Mcl-1 activity is the induction of ubiquitin-independent Mcl-1 degradation. Our own and other previous studies have demonstrated caspase-dependent generation of a 28kDa Mcl-1 fragment, Mcl-1128-350, which inhibits MM cell proliferation and survival. Here, we show that similar to bortezomib, the novel proteasome inhibitors carfilzomib and ixazomib, as well as staurosporine and adaphostin, induce the generation of Mcl-1128-350 in MM cells. Next, the molecular sequelae downstream of Mcl-1128-350, which mediate its pro-apoptotic activity, were delineated. Surprisingly, we observed nuclear accumulation of drug-induced or exogenously overexpressed Mcl-1128-350, followed by elevated mRNA and protein levels of c-Jun, as well as enhanced AP-1 reporter activity. Moreover, drug-induced AP-1 activity was blocked after introducing a point mutation into the highly conserved Mcl-1 caspase-cleavage site Asp127, but not Asp157. Consequently, drug-triggered cell death was significantly decreased in MM cells transfected with Mcl-1 D127A, but not with Mcl-1 D157A. Consistent with these data, treatment with bortezomib triggered c-Jun upregulation followed by apoptosis in Mcl-1wt/wt, but not Mcl-1δ/null murine embryonic fibroblasts (MEFs). Transfection of a plasmid carrying Mcl-1wt into Mcl-1δ/null MEFs restored bortezomib-induced Mcl-1 fragmentation, c-Jun upregulation and AP-1 reporter activity. Finally, our data indicate that drug-induced generation of a pro-apoptotic Mcl-1 fragment followed by c-Jun upregulation may also be a novel therapeutic approach in other tumor entities.

OriginalspracheEnglisch
Seiten (von - bis)286-294
Seitenumfang9
FachzeitschriftCancer Letters
Jahrgang343
Ausgabenummer2
DOIs
PublikationsstatusVeröffentlicht - 28 Feb. 2014
Extern publiziertJa

ASJC Scopus Sachgebiete

  • Onkologie
  • Krebsforschung

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