Phase I/II clinical trial of high-dose [I] meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding single myeloablative chemotherapy and haematopoietic stem cell transplantation.

Purpose: Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of high-dose I-meta-iodobenzylguanidine (I-mIBG) therapy combined with single high-dose chemotherapy (HDC) and haematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma in Japan.

Methods: Patients received 666 MBq/kg of I-mIBG and single HDC and HSCT from autologous or allogeneic stem cell sources.

Galectin-3 in angiogenesis and metastasis.

Galectin-3 is a member of the family of β-galactoside-binding lectins characterized by evolutionarily conserved sequences defined by structural similarities in their carbohydrate-recognition domains. Galectin-3 is a unique, chimeric protein consisting of three distinct structural motifs: (i) a short NH2 terminal domain containing a serine phosphorylation site; (ii) a repetitive proline-rich collagen-α-like sequence cleavable by matrix metalloproteases; and (iii) a globular COOH-terminal domain containing a carbohydrate-binding motif and an NWGR anti-death motif. It is ubiquitously expressed and has diverse biological functions depending on its subcellular localization.

Nuclear transport of galectin-3 and its therapeutic implications.

Galectin-3, a member of β-galactoside-binding gene family is a multi-functional protein, which regulates pleiotropic biological functions such as cell growth, cell adhesion, cell-cell interactions, apoptosis, angiogenesis and mRNA processing. Its unique structure enables it to interact with a plethora of ligands in a carbohydrate dependent or independent manner. Galectin-3 is mainly a cytosolic protein, but can easily traverse the intracellular and plasma membranes to translocate into the nucleus, mitochondria or get externalized.

Nucleoporin Nup98 mediates galectin-3 nuclear-cytoplasmic trafficking.

Nucleoporin Nup98 is a component of the nuclear pore complex, and is important in transport across the nuclear pore. Many studies implicate nucleoporin in cancer progression, but no direct mechanistic studies of its effect in cancer have been reported. We show here that Nup98 specifically regulates nucleus-cytoplasm transport of galectin-3, which is a ß-galactoside-binding protein that affects adhesion, migration, and cancer progression, and controls cell growth through the ß-catenin signaling pathway in cancer cells.

Regulation of autophagy by nucleoporin Tpr.

The nuclear pore complex (NPC) consists of a conserved set of ~30 different proteins, termed nucleoporins, and serves as a gateway for the exchange of materials between the cytoplasm and nucleus. Tpr (translocated promoter region) is a component of NPC that presumably localizes at intranuclear filaments. Here, we show that Tpr knockdown caused a severe reduction in the number of nuclear pores.

TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88.

MyD88, a Toll/interleukin-1 receptor homology (TIR) domain-containing adaptor protein, mediates signals from the Toll-like receptors (TLR) or IL-1/IL-18 receptors to downstream kinases. In MyD88-dependent TLR4 signaling, the function of MyD88 is enhanced by another TIR domain-containing adaptor, Mal/TIRAP, which brings MyD88 to the plasma membrane and promotes its interaction with the cytosolic region of TLR4. Hence, Mal is recognized as the "sorting adaptor" for MyD88.

RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis.

Chromosomal translocations involving chimeric fusions of the nucleoporin NUP98 protein have often been described in acute myelogenous leukemia (AML). All the fusion proteins have an identical NUP98 N terminus, which contains the GLEBS motif for interaction with the mRNA export factor RAE1 and FG repeats that associate with the transcription factors HDAC1 and p300. It is virtually unknown whether these interaction partners affect leukemogenesis.

The role of nuclear pore complex in tumor microenvironment and metastasis.

One of the main reasons for cancer mortality is caused by the highly invasive behavior of cancer cells, which often due to aggressive metastasis. Metastasis is mediated by various growth factors and cytokines, operating through numerous signaling pathways. Remarkably, all these metastatic signaling pathways must enter the nucleus through a single gatekeeper, the nuclear pore complex (NPC).

Unexpected role of nucleoporins in coordination of cell cycle progression.

Many human cancers have irregular chromosome content, a condition known as aneuploidy. Several nuclear pore proteins (nucleoporins/Nups) that mediate transport of RNA or macromolecules into and out of the nucleus have been implicated in mitosis. These nucleoporins are involved in molecular networks that function in a variety of mitotic processes, including chromosome condensation, sister chromatid cohesion, kinetochore assembly and spindle formation.

Nucleoporin translocated promoter region (Tpr) associates with dynein complex, preventing chromosome lagging formation during mitosis.

Gain or loss of whole chromosomes is often observed in cancer cells and is thought to be due to aberrant chromosome segregation during mitosis. Proper chromosome segregation depends on a faithful interaction between spindle microtubules and kinetochores. Several components of the nuclear pore complex/nucleoporins play critical roles in orchestrating the rapid remodeling events that occur during mitosis.

Phosphoglucose isomerase/autocrine motility factor mediates epithelial and mesenchymal phenotype conversions in breast cancer.

Phosphoglucose isomerase/autocrine motility factor (PGI/AMF) is a housekeeping gene product/cytokine that catalyzes a step in glycolysis and gluconeogenesis, and acts as a multifunctional cytokine associated with aggressive tumors. PGI/AMF has been correlated significantly with breast cancer progression and poor prognosis in breast cancer. We show here that ectopic expression of PGI/AMF induced epithelial-to-mesenchymal transition (EMT) in MCF10A normal human breast epithelial cells, and inhibition of PGI/AMF expression triggered mesenchymal-to-epithelial transition (MET) in aggressive mesenchymal-type human breast cancer MDA-MB-231 cells.

Autocrine motility factor stimulates the invasiveness of malignant cells as well as up-regulation of matrix metalloproteinase-3 expression via a MAPK pathway.

The autocrine motility factor (AMF) is a multifunctional protein that is involved in tumor progression including enhanced invasiveness via induction of matrix metalloproteinase-3 (MMP3). The increase in MMP3 was found in an AMF-high production tumor cell line, and c-Jun, c-Fos and mitogen-activated protein kinases (MAPKs) were also highly phosphorylated compared with the parent line. AMF stimulation induced the rapid phosphorylation of the cellular MAPK cascade and MMP3 secretion, which was blocked using a specific MAPK inhibitor.

Down-regulation of phosphoglucose isomerase/autocrine motility factor expression sensitizes human fibrosarcoma cells to oxidative stress leading to cellular senescence.

Phosphoglucose isomerase/autocrine motility factor (PGI/AMF) is a housekeeping gene product present in all cells, is an essential enzyme of catabolic glycolysis and anabolic gluconeogenesis, and regulates tumor cell growth and metastasis. Because glycolytic enzyme up-regulation of expression contributes to glycolytic flux, leading to increased of cell growth and a resistance to cellular stress of normal fibroblasts whereas down-regulation of PGI/AMF leads to mesenchymal-to-epithelial transition in tumor cells, we examined the involvement of PGI/AMF in overcoming cellular senescence in cancer cells. PGI/AMF cellular expression in HT1080 human fibrosarcoma was down-regulated by small interfering RNA methodology, which resulted in an increased sensitivity to oxidative stress and oxidative stress-induced cellular senescence.

Regulation of phosphoglucose isomerase/autocrine motility factor activities by the poly(ADP-ribose) polymerase family-14.

Phosphoglucose isomerase (PGI; EC 5.3.1.

The role of autocrine motility factor in tumor and tumor microenvironment.

Autocrine motility factor (AMF) is a tumor-secreted cytokine and is abundant at tumor sites, where it may affect the process of tumor growth and metastasis. AMF is a multifunctional protein capable of affecting cell migration, invasion, proliferation, and survival, and possesses phosphoglucose isomerase activity and can catalyze the step in glycolysis and gluconeogenesis. Here, we review the role of AMF and tumor environment on malignant processes.

Down-regulation of phosphoglucose isomerase/autocrine motility factor results in mesenchymal-to-epithelial transition of human lung fibrosarcoma cells.

Phosphoglucose isomerase (PGI) is one of the glycolytic enzymes and is a multifunctional enzyme that functions in glucose metabolism inside the cell while acting as a cytokine outside the cell, with properties that include autocrine motility factor (AMF) regulating tumor cell motility. Although there are many studies indicating that PGI/AMF has been implicated in progression of metastasis, no direct studies of the significance of exogenous PGI/AMF on tumor progression have been reported. Here, we report on the mesenchymal-to-epithelial transition (MET), which is the reverse phenomenon of the epithelial-to-mesenchymal transition that is associated with loss of cell polarity, loss of epithelia markers, and enhancement of cell motility essential for tumor cell invasion and metastasis.

Inhibition of breast tumor growth and angiogenesis by a medicinal herb: Ocimum gratissimum.

Ocimum sp. is a traditionally used medicinal herb, which shows anti-oxidant, anti-carcinogenic, radio-protective and free radical scavenging properties. So far no detailed studies have been reported on its effects on human cancers.

AMF/G6PI induces differentiation of leukemic cells via an unknown receptor that differs from gp78.

Autocrine Motility Factor (AMF)/maturation factor (MF)/neuroleukin (NLK) is a multifunctional protein, which acts as a glucose 6-phosphate isomerase (G6PI) intracellularly. Exto-G6PI stimulates invasion and metastasis of tumor cells, neurotropic growth and differentiation of leukemic cells. The cell motility and proliferation receptor is known to be gp78 (78 kilo-Dalton glycoprotein), which has seven transmembrane domains in its N-terminal region, but the maturation factor receptor remains unclear.

The autocrine motility factor (AMF) and AMF-receptor combination needs sugar chain recognition ability and interaction using the C-terminal region of AMF.

The autocrine motility factor (AMF) promotes cellular locomotion or invasion, and regulates tumor angiogenesis or ascites accumulation. These signals are triggered by binding between AMF and its receptor (AMFR), a glycoprotein on the cell surface. AMF has been identified as phosphohexose isomerase (PHI).

Crystal structures of mouse autocrine motility factor in complex with carbohydrate phosphate inhibitors provide insight into structure-activity relationship of the inhibitors.

Autocrine motility factor (AMF), a tumor-secreted cytokine, stimulates cell migration in vitro and metastasis in vivo. AMF is identical to the extracellular cytokines neuroleukin and maturation factor and, interestingly, to the intracellular enzyme phosphoglucose isomerase. The cytokine activity of AMF is inhibited by carbohydrate phosphate compounds as they compete for AMF binding with the carbohydrate moiety of the AMF receptor (AMFR), which is a glycosylated seven transmembrane helix protein.

Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia.

Phosphoglucose isomerase (PGI; EC 5.3.1.

Differential regulation of phosphoglucose isomerase/autocrine motility factor activities by protein kinase CK2 phosphorylation.

Phosphoglucose isomerase (PGI; EC 5.3.1.

Crystallization and preliminary X-ray crystallographic studies of mouse autocrine motility factor.

Mouse autocrine motility factor (mAMF), a tumour-secreted cytokine that stimulates cell migration in vitro and metastasis in vivo, has been crystallized by the hanging-drop vapour-diffusion method. The crystals belong to the monoclinic space group P2(1), with unit-cell parameters a = 69.97, b = 115.

Autocrine motility factor signaling induces tumor apoptotic resistance by regulations Apaf-1 and Caspase-9 apoptosome expression.

Autocrine motility factor (AMF) is a cytokine that regulates locomotion and metastasis of tumor cells. It is well known that expression levels of AMF secretion and its receptor (AMF R) are closely related to tumor malignancy and rheumatoid arthritis. We have established that AMF signaling induced anti-apoptotic activity and that human fibrosarcoma HT-1080 line that secreted high levels of AMF were resistant to drug-induced apoptosis.

Autocrine motility factor secreted by tumor cells upregulates vascular endothelial growth factor receptor (Flt-1) expression in endothelial cells.

The autocrine motility factor (AMF) is known as a cytokine regulating tumor cells motility via AMF receptor (AMFR) and promotes their metastasis. Recently, AMFRs have been found on the surface of host cells and it was showed that AMF possibly affects them. The signaling of AMF-AMFR in the host endothelial cells induces expression of a vascular endothelial growth factor receptor (VEGFR) Flt-1 and AMFR feedback that is regulated at the transcriptional level.