Up-regulation of c-Jun inhibits proliferation and induces apoptosis via caspase-triggered c-Abl cleavage in human multiple myeloma

Klaus Podar, Marc S Raab, Giovanni Tonon, Martin Sattler, Daniela Barilà, Jing Zhang, Yu-Tzu Tai, Hiroshi Yasui, Noopur Raje, Ronald A DePinho, Teru Hideshima, Dharminder Chauhan, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

56 Citations (Scopus)

Abstract

Here we show the antimyeloma cytotoxicity of adaphostin and carried out expression profiling of adaphostin-treated multiple myeloma (MM) cells to identify its molecular targets. Surprisingly, c-Jun was the most up-regulated gene even at the earliest point of analysis (2 h). We also observed adaphostin-induced c-Abl cleavage in immunoblot analysis. Proteasome inhibitor bortezomib, but not melphalan or dexamethasone, induced similar effects, indicating unique agent-dependent mechanisms. Using caspase inhibitors, as well as caspase-resistant mutants of c-Abl (TM-c-Abl and D565A-Abl), we then showed that c-Abl cleavage in MM cells requires caspase activity. Importantly, both overexpression of the c-Abl fragment or c-Jun and knockdown of c-Abl and c-Jun expression by small interfering RNA confirmed that adaphostin-induced c-Jun up-regulation triggers downstream caspase-mediated c-Abl cleavage, inhibition of MM cell growth, and induction of apoptosis. Finally, our data suggest that this mechanism may not only be restricted to MM but may also be important in a broad range of malignancies including erythroleukemia and solid tumors.

Original languageEnglish
Pages (from-to)1680-1688
Number of pages9
JournalCancer Research
Volume67
Issue number4
DOIs
Publication statusPublished - 15 Feb 2007
Externally publishedYes

Keywords

  • Adamantane/analogs & derivatives
  • Apoptosis/drug effects
  • Benzamides
  • Boronic Acids/pharmacology
  • Bortezomib
  • Caspase Inhibitors
  • Caspases/metabolism
  • Cell Growth Processes/drug effects
  • Dexamethasone/pharmacology
  • Humans
  • Hydroquinones/pharmacology
  • Imatinib Mesylate
  • Leukemia, Erythroblastic, Acute/drug therapy
  • Melphalan/pharmacology
  • Multiple Myeloma/drug therapy
  • Piperazines/pharmacology
  • Proto-Oncogene Proteins c-abl/genetics
  • Proto-Oncogene Proteins c-jun/biosynthesis
  • Pyrazines/pharmacology
  • Pyrimidines/pharmacology
  • Transfection
  • Up-Regulation/drug effects

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