Targeting the heat shock protein 90: a rational way to inhibit macrophage migration inhibitory factor function in cancer.
OBJECTIVE
Macrophage migration inhibitory factor (MIF), originally identified as a proinflammatory cytokine, is highly elevated in many human cancer types, independent of their histological origin. MIF's tumour promoting activities correlate with tumour aggressiveness and poor clinical prognosis. Genetic depletion of MIF in mouse cancer models results in significant inhibition of cell proliferation and induction of apoptosis, making it an attractive target for anticancer therapies. Here, we summarize the current possibilities to inhibit MIF function in cancer.


RESULTS
All known small molecule MIF inhibitors antagonize MIF's enzymatic function. However, a recent knockin mouse model suggested that protein interactions play a bigger biological role in tumour cell growth regulation than MIF's enzymatic activity. Thus, alternative strategies are important for targeting MIF. Recently, we identified that MIF in cancer cells is highly stabilized through the heat shock protein 90 machinery (HSP90). Thus, MIF is an HSP90 client. Pharmacological inhibition of the Hsp90 ATPase activity results in MIF degradation in several types of cancer cells. This provides a new way to inhibit MIF function independent of its enzymatic activity.


CONCLUSIONS
Targeting the HSP90 machinery is a promising way to inhibit MIF function in cancer. Along with MIF and dependent on the molecular make-up of the tumour, a large number of other critical tumourigenic proteins are also destabilized by HSP90 inhibition, overall resulting in a profound block of tumour growth.
aInstitute of Molecular Oncology, Göttingen Center of Molecular Biosciences, University of Göttingen, Göttingen, Germany bDepartment of Pathology, Stony Brook University, Stony Brook, New York, USA.
Ramona
R
Schulz
Ute M
UM
Moll
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D008263:Macrophage Migration-Inhibitory Factors; D009363:Neoplasm Proteins