This study investigated the
biological significance of the inhibition of
fatty acid synthase (FAS) in
multiple myeloma (MM) using the small molecule inhibitor
Cerulenin.
Cerulenin triggered growth inhibition in both MM cell lines and MM patient cells, and overcame the survival and growth advantages conferred by
interleukin-6,
insulin-like growth factor-1, and bone marrow stromal cells. It induced apoptosis in MM cell lines with only modest activation of
caspase -8, -9, -3 and PARP; moreover, the pan-
caspase inhibitor
Z-VAD-FMK did not inhibit
Cerulenin-induced apoptosis and cell death. In addition, treatment of MM cells with
Cerulenin primarily up-regulated
apoptosis-inducing factor/
endonuclease G, mediators of
caspase-independent apoptosis. Importantly,
Cerulenin induced endoplasmic reticulum stress response via up-regulation of the
Grp78/IRE1alpha/JNK pathway. Although the C-Jun-NH(2)-terminal
kinase (JNK) inhibitor SP600215 blocked
Cerulenin-induced cytotoxicity, it did not inhibit apoptosis and
caspase cleavage. Furthermore,
Cerulenin showed synergistic cytotoxic effects with various agents including
Bortezomib,
Melphalan and
Doxorubicin. Our results therefore indicate that inhibition of FAS by
Cerulenin primarily triggered
caspase-independent apoptosis and JNK-dependent cytotoxicity in MM cells. This report demonstrated that inhibition of FAS has anti-tumour activity against MM cells, suggesting that it represents a novel therapeutic target in MM.