http://www4.utsouthwestern.edu/moleculargenetics/pdf/msb_cur_res/2006%20CELL%20Goldstein%2035.pdf

Protein Sensors for Membrane Sterols

Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis. Several small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.

/pdf/glycolysis-inhibition-for-anticancer-treatment-40rjcq29jf.pdf

Glycolysis inhibition for anticancer treatment

To identify selective steps in metastasis, those that eliminate nonmetastatic tumor cells more efficiently than metastatic cells, we have evaluated the sequential dissemination of tumor cells from a mammary fatpad, using both metastatic (4T1 and 66cl4) and nonmetastatic (67NR, 168FARN, and 4TO7) subpopulations of a single mouse mammary tumor. Each of these variant subpopulations is resistant to one or more selective drugs so they could be quantitatively identified by colony formation in selective media. We found that the 2 metastatic cell lines metastasized by different routes and that the nonmetastatic tumor cell lines failed at different points in dissemination. Line 67NR did not leave the primary site; clonogenic tumor cells were not detected in the nodes, blood, or lungs during the experiment (7 weeks). Tumor line 168FARN disseminated from the primary tumor because clonogenic cells were cultured from the draining lymph nodes throughout the experiment. However, dissemination essentially stopped in the node as cells were rarely isolated from blood, lungs, or lives. Whether 168FARN cells failed to reach these tissues or were killed very rapidly after traversing the lymph node is unknown. Line 4TO7 cells disseminated via the blood and were consistently recovered from lungs by day 19 but failed to proliferate. This panel of 5 subpopulations thus identifies different points of selective failure in tumor cell dissemination and should be valuable in the assessment of antimetastatic therapies.

https://cancerres.aacrjournals.org/content/canres/52/6/1399.full.pdf

Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor.

Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness.

Positron emission tomography (PET) provides metabolic information that has been documented to be useful in patient care. The properties of positron decay permit accurate imaging of the distribution of positron-emitting radiopharmaceuticals. The wide array of positron-emitting radiopharmaceuticals has been used to characterize multiple physiologic and pathologic states. PET is used for characterizing brain disorders such as Alzheimer disease and epilepsy and cardiac disorders such as coronary artery disease and myocardial viability. The neurologic and cardiac applications of PET are not covered in this review. The major utilization of PET clinically is in oncology and consists of imaging the distribution of fluorine 18 fluorodeoxyglucose (FDG). FDG, an analogue of glucose, accumulates in most tumors in a greater amount than it does in normal tissue. FDG PET is being used in diagnosis and follow-up of several malignancies, and the list of articles supporting its use continues to grow. In this review, the ph...

Clinical Applications of PET in Oncology

To date, the structure of the autocrine motility factor (AMF), a tumorsecreted cytokine which stimulates cell migration in vitro and metastasis in vivo, is unknown. Here, AMF secreted by Gc-4 PF murine fibrosarcoma into a protein-free conditioned media was isolated, purified, and microsequenced. The results demonstrate that AMF is the previously cloned cytokine and enzyme designated as neuroleukin, and phosphohexose isomerase (PHI), which has been independently implicated in cell motility, and to be a cancer progression marker. PHI catalyzes isomerization of glucose 6-phosphate to fructose 6-phosphate and is specific for both sugars. Murine AMF exhibits the enzymatic properties of PHI and rabbit heart PHI-stimulated mouse fibrosarcoma cells9 motility similar to those of the endogenous AMF. Specific PHI inhibitors (carbohydrate phosphates) inhibited enzymatic activity and AMF-induced cell motility.

https://cancerres.aacrjournals.org/content/canres/56/13/2960.full.pdf

Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide.

Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor.

The results obtained from fragmented protein microsequencing have suggested that autocrine motility factor (AMF), a tumor-secreted Mr 55,000 cytokine that regulates cell motility in vitro as well as invasion and metastasis in vivo, is the neuroleukin (NLK)/phosphohexose isomerase (PHI)/maturation factor (MF) polypeptide. Here, we cloned, sequenced, and studied the expression, secretion, and distribution of AMF/NLK/PHI/MF in neoplastic and their normal counterpart cells. Although both normal and neoplastic cells express the gene product, overexpression associated with selective secretion of the protein was observed only in tumor cells. The cDNA sequences of AMF/NLK/PHI/MF found in both human cancer and normal cells were found to be identical, suggesting that its secretion by neoplastic cells is independent of mutation or alternative splicing. Immunohistochemical visualization has depicted AMF/NLK/PHI/MF to be localized into tubular-like vesicles, diffusely distributed throughout the cytoplasm and not colocalized with any particular cytoskeletal network. Confocal microscopic imaging had shown a partial colocalization between AMF and its receptor (Mr 78,000 glycoprotein), especially on the malignant cell surface periphery. The results suggest that extracellular AMF activity may be a result of the product of intracellular cleavage of a precursor polypeptide, which is overexpressed and selectively secreted through a nonclassical secretory mechanism by neoplastic cells.

https://cancerres.aacrjournals.org/content/canres/58/12/2667.full.pdf

Expression and secretion of neuroleukin/phosphohexose isomerase/maturation factor as autocrine motility factor by tumor cells.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2899%2900966-7

The autocrine motility factor receptor gene encodes a novel type of seven transmembrane protein

Tumor autocrine motility factor (AMF) is a cytokine which stimulates both random and directed cell migration by self-producing cells. AMF has been detected in and purified from serum-free conditioned medium of murine B16-F1 melanoma cells. Under nonreducing conditions AMF migrates in sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a single band of M r 55,000, whereas under reducing conditions it migrates as a single polypeptide of M r 64,000. Two-dimensional polyacrylamide gel electrophoresis of the purified AMF resolved two polypeptides with isoelectric points of 6.35 (major) and 6.4 (minor). No carbohydrate side chains were detected in the B16-F1 AMF. Purified AMF stimulated B16-F1 cell migration in a dose-dependent fashion and bound directly in a protein-protein-binding assay to the AMF receptor, a cell surface glycoprotein of M r 78,000 [glycoprotein (gp) 78]. The involvement of gp78 in AMF-stimulated function was demonstrated by motility assays. These results suggest that AMF is the natural ligand for the gp78-AMF receptor.

https://cancerres.aacrjournals.org/content/canres/51/13/3507.full.pdf

Hideomi Watanabe

Papers

Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide.

Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor.

Expression and secretion of neuroleukin/phosphohexose isomerase/maturation factor as autocrine motility factor by tumor cells.

The autocrine motility factor receptor gene encodes a novel type of seven transmembrane protein

Purification of B16-F1 melanoma autocrine motility factor and its receptor.