MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma

Abstract

Multiple myeloma (MM) remains largely incurable despite significant advances in bio- and chemotherapy. The major problem in MM management is development of drug resistance. Macrophage migration inhibitory factor (MIF) expression was significantly higher in purified MM cells from relapsed patients than those with sustained response, and high MIF MM patients had significantly shorter progression-free survival (PFS) and overall survival (OS). MM cell lines also express high levels of MIF, and knocking out MIF made them more sensitive to proteasome inhibitor (PI) induced apoptosis not observed with other chemotherapy drugs. Mechanistic studies showed that MIF protects MM cells from PI-induced apoptosis by maintaining mitochondrial function via suppression of superoxide production in response to PIs. Specifically, MIF, in the form of a homotrimer, acts as a chaperone for superoxide dismutase 1 (SOD1) to suppress PI-induced SOD1 misfolding and maintain SOD1 activity. MIF inhibitor 4-IPP and homotrimer disrupter ebselen, which do not kill MM cells, enhanced PI-induced SOD1 misfolding and loss of function, resulting in significantly more cell death in both cell lines and primary MM cells. More importantly, inhibiting MIF activity in vivo displayed synergistic antitumor activity with PIs and re-sensitized PI-resistant MM cells to treatment. In support of these findings, gene-profiling data showed a significantly negative correlation between MIF and SOD1 expression and response to PI treatment in MM patients. Hence, this study reveals that MIF plays a crucial role in MM sensitivity to PIs, and suggests that targeting MIF may be a promising strategy to (re)sensitize MM to the treatment.

Intratumor Heterogeneity of MIF Expression Correlates With Extramedullary Involvement of Multiple Myeloma

“…It is highlighted that MIF promotes progress and metastasis of various solid tumors, via activating downstream proliferation and anti-apoptotic signaling, regulating VEGF-mediated angiogenesis, inhibiting tumor suppressor P53, inducing immunosuppressive microenvironment and so on (36)(37)(38)(39)(40)(41)(42)(43). Pathogenic role of MIF has also been identified in MM, and its expression level may serve as a surrogate for disease progression and prognosis (18,34,(44)(45)(46). Recently, Wang et al reported that MIF was implicated in proteasome inhibitor resistance by maintaining superoxide dismutase 1 (SOD1) activity and mitochondrial function (44).…”

“…Pathogenic role of MIF has also been identified in MM, and its expression level may serve as a surrogate for disease progression and prognosis (18,34,(44)(45)(46). Recently, Wang et al reported that MIF was implicated in proteasome inhibitor resistance by maintaining superoxide dismutase 1 (SOD1) activity and mitochondrial function (44). In that sense, MIF High MM cells seem to be associated with more aggressive tumor behavior.…”

Molecular and pharmacological chaperones for SOD1

“…These results are indicative that, like hCCS, MIF-catalysed SOD1 disulphide formation is not wholly responsible for the SOD1 chaperone role. Preventing MIF trimer dissociation through an engineered inter-subunit disulphide between Cys80 and a mutated Asn110Cys site [48] does, however, consistently reduce mutant SOD1 misfolding and related cell death [44,47]. Trimeric MIF appears, therefore, to be the chaperone active species.…”

“…MIF is constitutively expressed by many tissue types including motor system cells but is conspicuously absent from neuronal cell bodies despite high-level MIF mRNA transcription [41,42]. In the absence of MIF, misfolded mutant SOD1 deposits are found on the cytoplasmic surface of mitochondria while, conversely, overexpression of MIF reduces mutant SOD1 association with both endoplasmic reticulum and mitochondrial membranes thereby maintaining mitochondrial function [42][43][44]. This translates into increased survival of mutant SOD1 expressing motor neurons when MIF production is increased.…”

The Role of Tumor Microenvironment in Multiple Myeloma Development and Progression

“…In fact, although M2 macrophages can be detected in BM from MM independently of the stage disease, the grade of infiltration and its correlation with poor prognosis is notable within relapsed MM patients compared to patients with MGUS or SMM [ 138 , 145 ]. In line with these data, some serum receptors such as soluble CD206 and CD163, as well as chemokines like CCL2 and MIF have been proposed as biomarkers for disease progression, prognosis and treatment response [ 38 , 146 , 147 , 148 ].…”