Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression

Ramona Schulz, et.al. 2012. J. Exp. Med. 209: 275-289

Speaker: Shih-Ying Wu (吳思瑩)                                  Time: 14:00-15:00 2012/02/22

Commentator: Dr. Chiou-Feng Lin (林秋烽老師)       Place: Room 601

Abstract:

Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine. It plays a causative role in many diseases, even including cancer. ^[1] It has long been known that MIF acts in many pathways to promote tumors. Besides, mRNA and protein expression level of MIF was increased in cancer cells. However, the mechanism is still unknown. The authors found that MIF protein was more stable in cancer cells than normal tissue. If MIF was silenced, the tumor cells would undergo apoptosis and clonogenicity was decreased. Thus, the authors hypothesized that MIF stabilization might be a result of protection from degradation by physical association with HSP90 chaperone complex. They found that MIF protein was destabilized after inhibiting HSP90 using 17-AGG and SAHA, HSP90 specific inhibitors, and that MIF was a novel HSP90 client as indicated by depletion of HSP90, HDAC6 or HSF1 by siRNA. Actually, MIF underwent proteasomal degradation during HSP90 inhibition. After silencing CHIP, MDM2, Parkin, or Cullin 5, E3 ligase was shown to play a role in proteasomal MIF degradation, in which only CHIP was required for MIFproteasomal degradation. Because excess MIF could rescue 17-AAG induced apoptosis and growth defects, the authors assumed that MIF degradation was the major route that mediated the cytotoxicity of 17-AAG. In MMTV-ErB2 mouse model of human HER2-positive breast cancer, MIF^-/-mice had much higher survival rate, longer tumor progression, and lower cell proliferation than MIF^+/+ mice, which was associated with p53 activation. However, the treatment of 17-AAG gave more remarkable efficacy of tumor growth inhibition in MIF^+/+ mice than MIF^-/- mice. This indicated that MIF was an important target of 17-AAG. In summary, HSP90 inhibition destabilized MIF, which could promote breast tumor survival. Thus targeting HSP90 might delay tumor progression and improve survival in breast cancer.

Reference:

1. Al-Abed Y, et.al. MIF as a disease target: ISO-1 as a proof-of-concept therapeutic. Future Med Chem., 2011. 3: 45-63.