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. Galectin-3 is mainly found in the cytoplasm, also seen in the nucleus and can be secreted by non-classical, secretory pathways. In general, secreted galectin-3 mediates cell migration, cell adhesion and cell-cell interactions through the binding with high affinity to galactose-containing glycoproteins on the cell surface. Cytoplasmic galectin-3 exhibits anti-apoptotic activity and regulates several signal transduction pathways, whereas nuclear galectin-3 has been associated with pre-mRNA splicing and gene expression. Its unique chimeric structure enables it to interact with a plethora of ligands and modulate diverse functions such as cell growth, adhesion, migration, invasion, angiogenesis, immune function, apoptosis and endocytosis emphasizing its significance in the process of tumor progression. In this review, we have focused on the role of galectin-3 in tumor metastasis with special emphasis on angiogenesis.

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. Our recent studies revealed that the nucleoporin, Rae1, plays critical roles in maintaining spindle bipolarity. Here, we show association of another nucleoporin, termed Tpr (translocated promoter region), with the molecular motors dynein and dynactin, which both orchestrate with the spindle checkpoints Mad1 and Mad2 during cell division. Overexpression of Tpr enhanced multinucleated cell formation. RNA interference-mediated knockdown of Tpr caused a severe lagging chromosome phenotype and disrupted spindle checkpoint proteins expression and localization. Next, we performed a series of rescue and dominant negative experiments to confirm that Tpr orchestrates proper chromosome segregation through interaction with dynein light chain. Our data indicate that Tpr functions as a spatial and temporal regulator of spindle checkpoints, ensuring the efficient recruitment of checkpoint proteins to the molecular motor dynein to promote proper anaphase formation.

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 epithelialto-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. EMT in MCF10A cells was shown by morphologic changes and loss of E-cadherin/B-catenin-mediated cellcell adhesion, which is concomitant with the induction of the E-cadherin transcriptional repressor Snail and proteosome-dependent degradation of B-catenin protein. Molecular analysis showed that PGI/AMF suppressed epithelial marker expressions and enhanced mesenchymal marker expressions. Silencing of PGI/AMF expression by RNA interference in MDA-MB-231 cells induced the reverse processes of EMT including altered cell shape, gain of epithelial marker, and reduction of mesenchymal marker, e.g., MET. Taken together, the results show the involvement of PGI/AMF in both EMT and MET: overexpression of PGI/AMF induces EMT in normal breast epithelial cells and reduction of PGI/AMF expression led to MET in aggressive breast cancer cells. These results suggest for the first time that PGI/AMF is a key gene to both EMT in the initiating step of cancer metastasis and MET in the later stage of metastasis during breast cancer progression.

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. These cells did not express the apoptotic protease activating factor-1 (Apaf-1) and Caspase-9 genes that encode for the proteins that form the "apoptosome" complex. The disappearance of the Apaf-1 and Caspase-9 gene was recovered by a cellular signaling inhibitor of protein kinase C, phosphatidylinositol 3-phosphate kinase and mitogen-activated protein kinase of the in vitro apoptosome Cancer is a disease in which down-regulation of apoptosis often occurs, and this often appears to compromise chemotherapy using anti-cancer drugs. It is well known that abnormal regulation of many mitochondria-related factors, such as Bcl-2, cytochrome c, Bax, Bik, Mn SOD, APAF-1 and Caspase-9, is observed in cancer cells. For example, the lack or loss of apoptotic proteinase activating factor-1 (Apaf-1) was observed in metastatic melanomas, which can contend with chemotherapy and are unable to execute the typical apoptotic programme in response to p53 activation. 1 Sensitivity to apoptosis induced by UV light dependent on its Apaf-1 deficiency level, 2 and over-expression of Apaf-1 induced etoposide-or paclitaxel-sensitive apoptosis, 3,4 have been reported in human leukemia cell lines. However, over-expression or experimental transduction of Apaf-1 and caspase-9 genes promoted the apoptotic sensitivities to radiation or the chemotherapeutic index of glioma cells. [5][6][7] Thus, the expression levels of Apaf-1 and caspase-9 in tumor cells seem to be important factors in determining the malignancy of the cells, and control of their expression may produce a therapeutic effect in clinical cancer treatments such as radiation and anti-cancer drugs. 8,9 Apaf-1 and caspase-9 are the core proteins of the "apoptosome" complex, which has an essential role in inducing mitochondrial programmed cell death. 10 It is necessary for the activation of pro-caspase-9 that cytochrome c and dATP interact with Apaf-1 as cofactors, and then the activated caspase-9 turns on the effector caspase-3 that then kills the cell by proteolysis. 11 Therefore, the apoptosome is a key molecular event of programmed cell death in several diseases that express an unusual apoptotic regulation, such as cancer. The function of the apoptosome is controlled by multiple molecules, transforming growth factor-beta up regulation via cytochrome c release, 12 heat shock protein 70 and 90 downregulation by binding to Apaf-1 and the formation of a cytosolic complex. [13][14][15] However, it is poorly understood at the molecular level why Apaf-1 and caspase-9 are decreased in malignant cells and how they regulate the function of the apoptosome. Ke...