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1.  A bis-Benzylidine Piperidone Targeting Proteasome Ubiquitin Receptor RPN13/ADRM1 as a therapy for cancer 
Cancer cell  2013;24(6):10.1016/j.ccr.2013.11.001.
The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of ubiquitin receptor RPN13 in the 19S regulatory particle and inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins. Multiple myeloma (MM) lines, even those resistant to bortezomib, were sensitive to RA190 via endoplasmic reticulum stress-related apoptosis. RA190 stabilized targets of human papillomavirus (HPV) E6 oncoprotein, and preferentially killed HPV-transformed cells. After oral (p.o.) or intraperitoneal (i.p.) dosing of mice, RA190 distributed to plasma and major organs excepting brain, and inhibited proteasome function in skin and muscle. RA190 administration profoundly reduced growth of multiple myeloma and ovarian cancer xenografts, and oral RA190 treatment retarded HPV16+ syngeneic mouse tumor growth, without impacting spontaneous HPV-specific CD8+ T cell responses, suggesting its therapeutic potential.
PMCID: PMC3881268  PMID: 24332045
Multiple Myeloma; Cervical Cancer; Ovarian Cancer; Proteasome Inhibitors; Ubiquitin Proteasome System (UPS); UPS-stress; RPN13; ubiquitin receptor
2.  Activation of Liver X Receptors inhibits of Hedgehog signaling, clonogenic growth, and self-renewal in multiple myeloma 
Molecular cancer therapeutics  2014;13(7):1873-1881.
The Hedgehog (Hh) signaling pathway is aberrantly activated in a wide variety of human cancers, and recent clinical studies have demonstrated that pathway inhibitors are effective in advanced basal cell carcinoma (BCC). The majority of these agents have been designed to target SMOOTHENED (SMO), a transmembrane regulator of Hh signaling, but subsequent mutations in SMO have been found to generate drug resistance. In other cancers, oncogenic events that bypass SMO may activate canonical Hh signaling, and SMO antagonists have not demonstrated significant activity in several diseases. Therefore, alternative strategies targeting the Hh pathway downstream of SMO may have clinical utility. Liver X Receptors (LXRs) regulate cholesterol and fatty acid homeostasis, and LXR activation can inhibit the Hh pathway in normal mouse embryonic fibroblasts. We examined the effects of LXR activation on Hh signaling in human multiple myeloma (MM) cells and found that LXR agonists inhibited Hh pathway activity and clonogenic tumor growth in vitro. LXR activation also inhibited putative MM cancer stem cells in vivo leading to the loss of tumor initiating and self-renewal potential. Finally, Hh signaling was inhibited downstream of SMO, suggesting that LXR agonists may represent a novel strategy to target pathogenic Hh signaling as well as treat MM.
PMCID: PMC4182725  PMID: 24807964
Liver X Receptors; Hedgehog pathway; multiple myeloma; cancer stem cells
3.  Development and Maintenance of Cancer Stem Cells under Chronic Inflammation 
Journal of Nihon Medical School  2011;78(3):138-145.
In many human cancers, tumorigenic potential is not equally shared by all cells but is restricted to phenotypically distinct subpopulations termed cancer stem cells. Cancer stem cells are also capable of both self-renewal and differentiation, and these functional properties have been suggested to play major roles in tumor initiation and progression. The factors responsible for the development of cancer stem cells and their subsequent regulation are unclear, but several chronic inflammatory states have been associated with an increased risk of malignancy. Therefore, it is possible that specific processes associated with chronic inflammation, as well as the adaptation to cellular stress, regulate cancer stem cells. Several factors associated with chronic inflammation, including cytokines, oxidative stress, and hypoxia, induce the activation of specific cellular response programs that can affect the survival, proliferation, metabolism, and differentiation of cancer cells, as well as the self-renewal and quiescence of normal stem cells. In this review, we discuss how these adaptive processes potentially become subverted to enhance the development and function of cancer stem cells.
PMCID: PMC3380605  PMID: 21720087
cancer stem cell; chronic inflammation
4.  Expression of growth differentiation factor 15 is not elevated in individuals with iron deficiency secondary to volunteer blood donation 
Transfusion  2010;50(7):1532-1535.
Low serum hepcidin levels provide a physiologic response to iron demand in patients with iron deficiency (ID). Based on a discovery of suppressed hepcidin expression by a cytokine named growth differentiation factor 15 (GDF15), it was hypothesized that GDF15 may suppress hepcidin expression in humans with ID due to blood loss.
To test this hypothesis, GDF15 and hepcidin levels were measured in peripheral blood from subjects with iron-deficient erythropoiesis before and after iron supplementation.
Iron variables and hepcidin levels were significantly suppressed in iron-deficient blood donors compared to healthy volunteers. However, ID was not associated with elevated serum levels of GDF15. Instead, iron-deficient subjects’ GDF15 levels were slightly lower than those measured in the control group of subjects (307 ± 90 and 386 ± 104 pg/mL, respectively). Additionally, GDF15 levels were not significantly altered by iron repletion.
ID due to blood loss is not associated with a significant change in serum levels of GDF15.
PMCID: PMC3282986  PMID: 20210929
Bju International  2011;107(4):678-679.
PMCID: PMC3277454  PMID: 21276178
6.  Growth differentiation factor 15 in erythroid health and disease 
Current opinion in hematology  2010;17(3):184-190.
Purpose of review
Growth differentiation factor 15 (GDF15) was identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. This review addresses the regulation, expression and potential functions of GDF15 in the context of erythroid biology.
Recent findings
GDF15 expression during late erythroid differentiation was discovered as part of an erythroblast transcriptome project. Since GDF15 expression is associated with cellular stress or apoptosis, further investigation of the cytokine was focused upon its involvement in ineffective erythropoiesis. Remarkably high serum levels were detected in patients with thalassemia syndromes, congenital dyserythropoiesis and some acquired sideroblastic anemias. Similarly high-level GDF15 expression is not a feature of normal erythropoiesis, or erythroid recovery after bone marrow transplantation. Since GDF15 is a TGF-β superfamily member, it was investigated as an effector of ineffective erythropoiesis that suppresses hepcidin expression despite iron overloading.
In contrast to the low-levels of GDF15 expressed during normal erythropoiesis, ineffective erythropoiesis causes high-level expression of GDF15. In patients with thalassemia and related anemias, GDF15 expression may contribute to iron overloading or other features of the disease phenotype.
PMCID: PMC2884377  PMID: 20182355
GDF15; ineffective erythropoiesis; iron regulation
7.  Iron Loading and Overloading due to Ineffective Erythropoiesis 
Advances in Hematology  2010;2010:358283.
Erythropoiesis describes the hematopoietic process of cell proliferation and differentiation that results in the production of mature circulating erythrocytes. Adult humans produce 200 billion erythrocytes daily, and approximately 1 billion iron molecules are incorporated into the hemoglobin contained within each erythrocyte. Thus, iron usage for the hemoglobin production is a primary regulator of plasma iron supply and demand. In many anemias, additional sources of iron from diet and tissue stores are needed to meet the erythroid demand. Among a subset of anemias that arise from ineffective erythropoiesis, iron absorption and accumulation in the tissues increases to levels that are in excess of erythropoiesis demand even in the absence of transfusion. The mechanisms responsible for iron overloading due to ineffective erythropoiesis are not fully understood. Based upon data that is currently available, it is proposed in this review that loading and overloading of iron can be regulated by distinct or combined mechanisms associated with erythropoiesis. The concept of erythroid regulation of iron is broadened to include both physiological and pathological hepcidin suppression in cases of ineffective erythropoiesis.
PMCID: PMC2868182  PMID: 20467559

Results 1-7 (7)