Up-regulation of c-Jun inhibits proliferation and induces apoptosis via caspase-triggered c-Abl cleavage in human multiple myeloma.
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.
Podar
Klaus
K
Jerome Lipper Multiple Myeloma Center, Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. klaus_podar@dfci.harvard.edu
Raab
Marc S
MS
Tonon
Giovanni
G
Sattler
Martin
M
Barilà
Daniela
D
Zhang
Jing
J
Tai
Yu-Tzu
YT
Yasui
Hiroshi
H
Raje
Noopur
N
DePinho
Ronald A
RA
Hideshima
Teru
T
Chauhan
Dharminder
D
Anderson
Kenneth C
KC
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001549:Benzamides; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008558:Melphalan / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
D001549:Benzamides; D001897:Boronic Acids; D061945:Caspase Inhibitors; D006873:Hydroquinones; C404397:NSC 680410; D010879:Piperazines; D016755:Proto-Oncogene Proteins c-jun; D011719:Pyrazines; D011743:Pyrimidines; D000069286:Bortezomib; D003907:Dexamethasone; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D020169:Caspases; D000218:Adamantane; D008558:Melphalan