Rapid, cell surface-initiated, pregenomic androgen actions have been described in various vertebrate cells, but the receptors mediating these actions remain unidentified. We report here the cloning and expression of a cDNA from Atlantic croaker (Micropogonias undulatus) ovaries encoding a 33-kDa, seven-transmembrane protein with binding and signaling characteristics of a membrane androgen receptor that is unrelated to any previously described steroid receptor. Instead, croaker membrane androgen receptor has 81–93% amino acid sequence identity with zinc transporter ZIP9 (SLC39A9) subfamily members, indicating it is a ZIP9 protein. Croaker ZIP9 is expressed in gonadal tissues and in brain and is up-regulated in the ovary by reproductive hormones. Croaker ZIP9 protein is localized to plasma membranes of croaker granulosa cells and human breast cancer (SKBR-3) cells stably transfected with ZIP9. Recombinant croaker ZIP9 has a high affinity (dissociation constant, K_d, 12.7 nM), limited capacity (maximal binding capacity 2.8 nM/mg protein), displaceable, single binding site-specific for androgens, characteristic of steroid receptors. Testosterone activates a stimulatory G protein coupled to ZIP9, resulting in increased cAMP production. Testosterone promotes serum starvation-induced cell death and apoptosis in transfected cells and in croaker ovarian follicle cells that is associated with rapid increases in intracellular free zinc concentrations, suggesting an involvement of zinc in this nonclassical androgen action to promote apoptosis. These responses to testosterone are abrogated by treatment with ZIP9 small interfering RNA. The results provide the first evidence that zinc transporter proteins can function as specific steroid membrane receptors and indicate a previously unrecognized signaling pathway mediated by steroid receptors involving alterations in intracellular zinc.

The transcription factor, forkhead box M1 (FOXM1), has been implicated in the natural history and outcome of newly diagnosed high-risk myeloma (HRMM) and relapsed/refractory myeloma (RRMM), but the mechanism with which FOXM1 promotes the growth of neoplastic plasma cells is poorly understood. Here we show that FOXM1 is a positive regulator of myeloma metabolism that greatly impacts the bioenergetic pathways of glycolysis and oxidative phosphorylation (OxPhos). Using FOXM1-deficient myeloma cells as principal experimental model system, we find that FOXM1 increases glucose uptake, lactate output, and oxygen consumption in myeloma. We demonstrate that the novel 1,1-diarylethylene small-compound FOXM1 inhibitor, NB73, suppresses myeloma in cell culture and human-in-mouse xenografts using a mechanism that includes enhanced proteasomal FOXM1 degradation. Consistent with the FOXM1-stabilizing chaperone function of heat shock protein 90 (HSP90), the HSP90 inhibitor, geldanamycin, collaborates with NB73 in slowing down myeloma. These findings define FOXM1 as a key driver of myeloma metabolism and underscore the feasibility of targeting FOXM1 for new approaches to myeloma therapy and prevention.

We assessed differences in survival between non-Hispanic black (NHB) and non-Hispanic white (NHW) patients with multiple myeloma (MM), and the sequential effects of patient characteristics, and diagnosis and treatment-related factors on the survival disparity using data from 3319 NHB and 20,831 NHW MM patients in the SEER-Medicare (1999–2017) database. Four sets of 3319 NHWs were matched sequentially to the same set of 3319 NHBs, based on demographics (age, sex, year of diagnosis, marital status, and SEER site), socioeconomic status (SES, demographics plus SES), presentation factors (SES variables plus comorbidity), and treatment factors (presentation variables plus antimyeloma therapies). We found NHBs were less likely to receive treatment than NHWs even among patients matched for demographics, SES, and comorbidities. The absolute difference in 5-year survival between NHBs and NHWs was not significant in the demographics match (0.6%; P = 0.30) and remained non-significant after matching for SES (1.4%, P = 0.17). When matching for presentation, NHBs had significantly longer 5-year survival than NHWs (absolute difference = 3.8%, P = 0.003). Additional matching on treatment-related factors further enlarged the racial difference in 5-year survival to 4.6% (P < 0.001). Our findings reinforce the importance of equitable access to effective treatment modalities to further improve the survival of NHB patients with MM.

Multiple myeloma (MM) is a blood cancer characterized by the accumulation of malignant monoclonal plasma cells in the bone marrow. It develops through a series of premalignant plasma cell dyscrasia stages, most notable of which is the Monoclonal Gammopathy of Undetermined Significance (MGUS). Significant advances have been achieved in uncovering the genomic aberrancies underlying the pathogenesis of MGUS-MM. In this review, we discuss in-depth the genomic evolution of MM and focus on the prognostic implications of the accompanied molecular and cytogenetic aberrations. We also dive into the latest investigatory techniques used for the diagnoses and risk stratification of MM patients.