Autocrine motility factor and its receptor expression in musculoskeletal tumors.

Management of aggressive malignant musculoskeletal tumors is clinically challenging and awaits the identification of regulator(s) that can be therapeutically used to improve patient outcome. Autocrine motility factor (AMF), a secreted cytokine, is known to alter the bone microenvironment by linking to its receptor AMFR (AMF Receptor), leading to tumor progression. It was noted that both the ligand and its receptor belong to the moonlighting family of proteins, as they contribute to intracellular metabolic function such as glycolysis and gluconeogenesis by expressing glucose-6-phosphate isomerase AMF/GPI and higher protein degradation by expressing AMFR/gp78 functioning as ubiquitin ligase activity. Thus, AMF/GPI and AMFR/gp78 contribute to higher metabolic turnover of protein and glucose. Recently, a large-scale cohort study including 23 different histological types of musculoskeletal tumors revealed that patients with osteosarcoma, multiple myeloma, rhabdomyosarcoma, and angiosarcoma tend to express higher levels of AMF, whereas multiple myeloma patients expressed high levels of AMFR. Consistently, the cellular data showed that a variety of musculoskeletal tumors express AMF and components of bone microenvironment express AMFR. Thus, a novel outlook suggests a cellular link and cross-talk between musculoskeletal tumors and the skeletal milieu are regulated by AMF-AMFR signaling. This review will highlight the pharmacological need for AMF and AMFR inhibitors as unmet medical needs for patients with malignant musculoskeletal tumors.

Amplification of autocrine motility factor and its receptor in multiple myeloma and other musculoskeletal tumors.

Autocrine motility factor (AMF: GPI) and its receptor AMFR (AMF Receptor: gp78) regulate the metastatic process. Here, we have tested the expression levels of AMF, AMFR, and AMF × AMFR in 1348 patients with musculoskeletal tumor. The results depicted here identified that multiple myeloma highly express AMF × AMFR value as compared with normal bone samples (p < 0.00001). To visualize the AMF × AMFR autocrine amplification in multiple myeloma microenvironment, we have developed a novel software aimed at analyzing numerous cell-to-cell and ligand-to-receptor interactions, i.e., Environmentome. It has led to the identification that myeloma-associated interactions with normal bone cells including osteoblast, osteoclast, immunological components, and others in a paracrine manner. In conclusion, the data showed that AMF × AMFR amplification is a clinical manifestation in bone microenvironment of multiple myeloma.

Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications.

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions.

Betulinic Acid Exerts Cytotoxic Activity Against Multidrug-Resistant Tumor Cells via Targeting Autocrine Motility Factor Receptor (AMFR).

Betulinic acid (BetA) is a naturally occurring pentacyclic triterpene isolated from the outer bark of white-barked birch trees and many other medicinal plants. Here, we studied betulinic acid's cytotoxic activity against drug-resistant tumor cell lines. P-glycoprotein (MDR1/ABCB1) and BCRP (ABCG2) are known ATP-binding cassette (ABC) drug transporters that mediating MDR. ABCB5 is a close relative to ABCB1, which also mediates MDR. Constitutive activation of the EGF receptor is tightly linked to the development of chemotherapeutic resistance. BetA inhibited P-gp, BCRP, ABCB5 and mutation activated EGFR overexpressing cells with similar efficacy as their drug-sensitive parental counterparts. Furthermore, the mRNA expressions of ABCB1, BCRP, ABCB5 and EGFR were not related to the 50% inhibition concentrations (IC50) for BetA in a panel of 60 cell lines of the National Cancer Institute (NCI), USA. In addition to well-established MDR mechanisms, we attempted to identify other molecular mechanisms that play a role in mediating BetA's cytotoxic activity. For this reason, we performed COMPARE and hierarchical cluster analyses of the transcriptome-wide microarray-based mRNA expression of the NCI cell lines panel. Various genes significantly correlating to BetA's activity were involved in different biological processes, e.g., cell cycle regulation, microtubule formation, signal transduction, transcriptional regulation, chromatin remodeling, cell adhesion, tumor suppression, ubiquitination and proteasome degradation. Immunoblotting and in silico analyses revealed that the inhibition of AMFR activity might be one of the mechanisms for BetA to overcome MDR phenotypes. In conclusion, BetA may have therapeutic potential for the treatment of refractory tumors.

Association between autocrine motility factor receptor gene polymorphism (rs2440472, rs373191257) and glioblastoma multiform in a representative Iranian population.

BACKGROUND: Glioblastoma multiform (GBM) is the most common and most malignant of the glial tumors that begins primarily in brain tissue. Genetic background could be considered as an important predisposing factor in GBM. Autocrine motility factor receptor (AMFR) is a cytokine receptor that participates in a lot of physiologic and pathologic processes like: Cellular motility and metastasis. So, it seems that this protein has an essential role in pathophysiology of several cancers and could be a potential diagnostic and or therapeutic target in GBM. The aim of this study is to investigate the association of AMFR (rs2440472, rs373191257) gene polymorphism and GBM in a representative Iranian population. MATERIALS AND METHODS: This study includes 81 cases of GBM and 117 control subjects. After DNA extraction, polymerase chain reaction - high resolution melting reaction was performed. For each single nucleotide polymorphisms, 12 samples were selected for sequencing. Data was analyzed using Chi-square test and Logistic regression. RESULTS: For rs2440472, frequency of GG genotype in the case group was increased compared to the control group (51.9% vs. 34.2% respectively, P = 0.013). After adjusting for sex and age by logistic regression our results were the same (P = 0.017, odds ratio = 2.056). Allelic frequencies for rs2440472 among cases and controls were not significantly different (P = 0.058). For rs373191257, genotypic and allelic frequencies were not significantly different between two groups. CONCLUSION: Our results showed the possible association between the AMFR rs2440472 gene polymorphism with susceptibility to GBM.

Prognostic significance of autocrine motility factor receptor expression by colorectal cancer and lymph node metastases.

BACKGROUND: Autocrine motility factor receptor (AMFR) has been linked to metastasis and tumorigenicity. The aim of this study was to evaluate expression and prognostic significance of AMFR in colorectal carcinoma. METHODS: AMFR expression was evaluated in 127 colon cancer specimens, 131 rectal cancer specimens, and 47 colonic and 25 rectal corresponding lymph node metastases. Clinicopathological correlates of prognostic significance were established by univariate and multivariate analysis. Spearman's correlation determined the association of expression between cancers and their metastases. RESULTS: AMFR was over-expressed by 22% of colon cancers and 18% of rectal cancers. AMFR over-expression correlated significantly with improved disease-free survival (DFS) (P < .05) in colon cancer and decreased DFS in corresponding nodal metastases. In rectal cancer, AMFR over-expression significantly correlated with decreased overall survival, DFS, and disease-specific survival (P < .001, P = .031, P = .005, respectively) and decreased overall survival in corresponding metastases. CONCLUSION: AMFR may serve as a molecular prognosticator for colon cancer and rectal cancer.

Research progress in the relationship of autocrine motility factor,autocrine motility factor receptor and the nervous system / 中国药理学通报

Autocrine motility factor (AMF) plays an important role in the stimulation of the migration and motility of cells, especially the generation, migration and angiogenesis of tumor. Recently, it has been found that AMF has three isoforms, ATX-t, ATX-m and PD-I alpha. The PD-I alpha isoform is specifically expressed in the brain, which plays extensive functions in nervous system, such as regulating neural development and differentiation, promoting neurotrauma repair, inducing neuropathic pain, even contributing neurodegeneration under some circumstances. This indicates the close relationship of AMF/AMFR and the pathophysiology of the nervous system. This paper mainly reviews the function of AMF and AMFR and its possible mechanism in the nervous system.