Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the course of oncogenesis and tumor progression, cancer cells constitutively upregulate signaling pathways relevant to cell proliferation and survival as a strategy to overcome genomic instability and acquire resistance phenotype to chemotherapeutic agents. In light of this clinical and molecular heterogeneity of human cancers, it is desirable to concomitantly target these genetic abnormalities by using an agent with pleiotropic mode of action. Indole-3-carbinol and its metabolite 3,3'-diindoylmethane (DIM) target multiple aspects of cancer cell-cycle regulation and survival including Akt-NF kappa B signaling, caspase activation, cyclin-dependent kinase activities, estrogen metabolism, estrogen receptor signaling, endoplasmic reticulum stress, and BRCA gene expression. This broad spectrum of anti-tumor activities in conjunction with low toxicity underscores the translational value of indole-3-carbinol and its metabolites in cancer prevention/therapy. Furthermore, novel anti-tumor agents with overlapping underlying mechanisms have emerged via structural optimization of indole-3-carbinol and DIM, which may provide considerable therapeutic advantages over the parental compounds with respect to chemical stability and anti-tumor potency. Together, these agents might foster new strategies for cancer prevention and therapy.
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PMID:Indole-3-carbinol as a chemopreventive and anti-cancer agent. 1831 59

Poorly formed tumor blood vessels lead to regions of microenvironmental stress due to depletion of oxygen and glucose and accumulation of waste products (acidosis). These conditions contribute to tumor progression and correlate with poor patient prognosis. Here we show that the microenvironmental stresses found in the solid tumor are able to inhibit the canonical Wnt/beta-catenin signaling pathway. However, tumor cells harboring common beta-catenin pathway mutations, such as loss of adenomatous polyposis coli, are insensitive to this novel hypoxic effect. The underlying mechanism responsible is hypoxia-induced endoplasmic reticulum (ER) stress that inhibits normal Wnt protein processing and secretion. ER stress causes dissociation between GRP78/BiP and Wnt, an interaction essential for its correct posttranslational processing. Microenvironmental stress can therefore block autocrine and paracrine signaling of the Wnt/beta-catenin pathway and negatively affect tumor growth. This study provides a general paradigm relating oxygen status to ER function and growth factor signaling.
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PMID:Tumor hypoxia blocks Wnt processing and secretion through the induction of endoplasmic reticulum stress. 1882 43

Previous studies have demonstrated that gamma-synuclein is overexpressed in a variety of human malignancies. Overexpression of gamma-synuclein in human breast cancer cells leads to an increase in cell motility, resistance to chemotherapeutic drugs, and mitotic checkpoint dysfunction. We report in this study that gamma-synuclein is up-regulated by endoplasmic reticulum stress. The up-regulation of gamma-synuclein expression by endoplasmic reticulum stress is mediated, at least in part, by activation transcription factor (ATF) 4. Knockdown of gamma-synuclein sensitized human breast cancer cells to endoplasmic reticulum stress-induced apoptosis. Induction of apoptosis by endoplasmic reticulum stress when gamma-synuclein was inhibited was dependent on JNK or caspase activation, with caspase-3 and caspase-7 being involved. Treatment with the JNK or caspase-3 and caspase-7 inhibitor partially blocked endoplasmic reticulum stress-induced apoptosis in breast cancer cells transfected with or without the siRNA against gamma-synuclein. Taken together, these data suggest that gamma-synuclein may promote cancer progression by suppressing endoplasmic reticulum stress-induced apoptosis.
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PMID:Up-regulation of gamma-synuclein contributes to cancer cell survival under endoplasmic reticulum stress. 1900 86

Hypoxia is a dynamic feature of the tumor microenvironment that contributes to drug resistance and cancer progression. We previously showed that components of the unfolded protein response (UPR), elicited by endoplasmic reticulum (ER) stress, are also activated by hypoxia in vitro and in vivo animal and human patient tumors. Here, we report that ER stressors, such as thapsigargin or the clinically used proteasome inhibitor bortezomib, exhibit significantly higher cytotoxicity toward hypoxic compared with normoxic tumor cells, which is accompanied by enhanced activation of UPR effectors in vitro and UPR reporter activity in vivo. Treatment of cells with the translation inhibitor cycloheximide, which relieves ER load, ameliorated this enhanced cytotoxicity, indicating that the increased cytotoxicity is ER stress-dependent. The mode of cell death was cell type-dependent, because DLD1 colorectal carcinoma cells exhibited enhanced apoptosis, whereas HeLa cervical carcinoma cells activated autophagy, blocked apoptosis, and eventually led to necrosis. Pharmacologic or genetic ablation of autophagy increased the levels of apoptosis. These results show that hypoxic tumor cells, which are generally more resistant to genotoxic agents, are hypersensitive to proteasome inhibitors and suggest that combining bortezomib with therapies that target the normoxic fraction of human tumors can lead to more effective tumor control.
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PMID:Preferential cytotoxicity of bortezomib toward hypoxic tumor cells via overactivation of endoplasmic reticulum stress pathways. 1901 Sep 6

GRP78/BiP is a major endoplasmic reticulum (ER) chaperone protein critical for protein quality control of the ER, as well as controlling the activation of the ER-transmembrane signaling molecules. Through creation of mouse models targeting the Grp78 allele, the function of GRP78 in development and disease has been investigated. These led to the discovery that GRP78 function is obligatory for early embryonic development. However, in adult animals, GRP78 is preferably required for cancer cell survival under pathologic conditions such as tumor progression and drug resistance. The discovery of surface localization of GRP78 in cancer cells reveals potential novel function, interaction with cell-surface receptors, and possible therapeutic implications. Mouse models also reveal that GRP78 controls maturation and secretion of neuronal factors for proper neural migration and offers neuroprotection.
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PMID:Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. 1930 59

Muc4 is a heterodimeric membrane mucin implicated in epithelial differentiation and tumor progression. It is expressed from a single gene as a 300 kDa precursor protein which is cleaved in the endoplasmic reticulum to its two subunits. Our previous work has shown that Muc4 is regulated by TGFbeta, which represses the precursor cleavage. Working with Muc4-transfected A375 tumor cells, we now show that Muc4 undergoes proteosomal degradation. Proteosome inhibitors prolong the life of the precursor, shunt the Muc4 into cytoplasmic aggresomes, increase the level of Muc4 associated with the endoplasmic reticulum chaperones calnexin and calreticulin and increase the levels of ubiquitinated Muc4. Most importantly, proteosome inhibitors repress the TGFbeta inhibition of Muc4 expression. These results suggest a model in which TGFbeta inhibits precursor cleavage, shunting the precursor into the proteosomal degradation pathway. Thus, the cells have evolved a mechanism to use the quality control pathway for glycoproteins to control the quantity of the protein produced.
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PMID:TGFbeta regulation of membrane mucin Muc4 via proteosome degradation. 1938 4

Hypoxia/anoxia promotes tumor aggressiveness and negatively impacts tumor response to therapy. Coordinate regulation of HIF-dependent and HIF-independent pathways has been shown to contribute to cellular adaptation to hypoxic stress, and to couple macromolecular synthesis rates to reduced energy availability. An important component of this type of adaptation is the activation of the endoplasmic reticulum kinase PERK by acute or prolonged hypoxia. Activated PERK subsequently induces phosphorylation of the translation initiation factor eIF2alpha and translational upregulation of the transcription factor ATF4. ATF4 is a basic leucine-zipper (bZip) transcription factor, which regulates amino acid metabolism, cellular redox state, and anti-stress responses. ATF4 expression can be regulated at transcriptional, translational, and post-translational levels. The functional activation of ATF4 under hypoxia and the overexpression of ATF4 in hypoxic areas of clinical samples of human tumors suggest that ATF4 plays a role in tumor hypoxic adaptation. Here we summarize recent findings regarding the regulation of ATF4 in transformed cells, clinical tumor samples and tumor models, and speculate on its potential role in tumor progression and chemoresistance.
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PMID:ATF4, an ER stress and hypoxia-inducible transcription factor and its potential role in hypoxia tolerance and tumorigenesis. 1951 98

Phosphoglucose isomerase (PGI) is a glycolytic enzyme that exhibits a dual function as an extracellular cytokine, under the name autocrine motility factor (AMF). Its cell surface receptor, gp78/AMFR, is also localized to the endoplasmic reticulum where it functions as an E3 ubiquitin ligase. Expression of both AMF/PGI and gp78/AMFR is associated with cancer and, in this review, we will discuss various aspects of the biology of this ligand-receptor complex and its role in tumor progression.
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PMID:The complex biology of autocrine motility factor/phosphoglucose isomerase (AMF/PGI) and its receptor, the gp78/AMFR E3 ubiquitin ligase. 1960 12

The galectins, a family of lectins, modulate distinct cellular processes, such as cancer progression, immune response and cellular development, through their specific binding to extracellular or intracellular ligands. In the past few years, research has unravelled interactions of different galectins with lipids and glycoproteins in the outer milieu or in the secretory pathway of cells. Interestingly, these lectins do not possess a signalling sequence to enter the endoplasmic reticulum as a starting point for the classical secretory pathway. Instead they use a so-called non-classical mechanism for translocation across the plasma membrane and/or into the lumen of transport vesicles. Here, they stabilize transport platforms for apical trafficking or sort apical glycoproteins into specific vesicle populations. Modes of ligand interaction as well as the modulation of binding activities and trafficking pathways are discussed in this review.
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PMID:The role of galectins in protein trafficking. 1965 Aug 51

We identified that whirlin is localized to chromosome 9q32-33, and is up-regulated in colorectal cancer tissues by using oligonucleotide array techniques and the Sosui system (http://www.tuat.ac.jp/~mitaku/sosui/). The deduced 920-amino acid protein encoded by the whirlin gene contains three PDZ domains and a proline-rich region that separates PDZ2 from PDZ3, which is located at the C terminus. As previously reported, human whirlin gene is alternatively spliced to form a long and a short transcript in situ hybridization. The sequence of the encoded protein shows that the short C-terminal isoform contains one PDZ domain and the proline-rich domain (whirlin isoform 2), whereas the long isoform is composed of all three PDZ domains and the proline-rich domain (whirlin isoform 1). The gene expression of whirlin was found to be up-regulated in colorectal cancer tissues compared with matched normal colon tissues by semi-quantitative RT-PCR (P<0.05). Western blotting detected whirlin protein with a molecular mass of 49.3 kDa in colorectal cancer samples, suggesting that the whirlin protein overexpressed in colorectal cancer samples is the short C-terminal isoform 2. Its expression was recognized in colorectal cancer cell lines and was increased in accordance with tumor progression in colorectal cancer patients. Immunohistochemistry showed high levels of staining for whirlin isoform 2 only in the mucosal glands in colon cancers, but this protein was barely detected in normal colonic glands. Immunoelectron microscopic findings showed that whirlin isoform 2 is localized on plasma membranes and endoplasmic reticulum membranes, but not in the nuclei. Tissue microarrays showed that whirlin isoform 2 is abundantly expressed in colon cancers with lymph node metastasis compared with those without lymph node metastasis, and overexpression of this protein was associated with tumor progression. In conclusion, we demonstrated that whirlin isoform 2 is highly expressed in colon cancer tissues and that it is related to tumor progression.
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PMID:Overexpression of the signal peptide whirlin isoform 2 is related to disease progression in colorectal cancer patients. 1972 6


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