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)

Hypoxia, a key microenvironmental factor for tumor development, not only stimulates angiogenesis and glycolysis for tumor expansion, but also induces cell cycle arrest and genetic instability for tumor progression. Several independent studies have shown hypoxic blockade of cell cycle progression at the G1/S transition, arising from the inactivation of S-phase-promoting cyclin E-CDK2 kinase complex. Despite these findings, the biochemical pathways leading to the cell cycle arrest remain poorly defined. We recently showed that hypoxic activates the expression of CDNK1A encoding the CDK2 inhibitor p21Cip1, through a novel HIF-1alpha-Myc pathway that involves Myc displacement from the CDNK1A promoter by the hypoxia-inducible transcription factor HIF-1alpha. In pursuit of further understanding of the hypoxic effects on cell cycle in tumor cells, here we report that hypoxia inhibits the expression of CDC25A, another cell cycle gene encoding a tyrosine phosphatase that maintains CDK2 activity. In accordance with the HIF-1alpha-Myc pathway, hypoxia requires HIF-1alpha for CDC25A repression, resulting in a selective displacement of an activating Myc from the CDC25A promoter without affecting a canonical Myc binding in the intron. Intriguingly, HIF-1alpha alone fails to recapitulate the hypoxic effect, indicating that HIF-1alpha is necessary but insufficient for the hypoxic repression. Taken together, our studies indicate that hypoxia inhibits cell cycle progression by controlling the expression of various cell cycle genes.
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PMID:Hypoxic suppression of the cell cycle gene CDC25A in tumor cells. 1767 23

Centrosomes play a critical role in formation of bipolar mitotic spindles, an essential event for accurate chromosome segregation into daughter cells. Numeral abnormalities of centrosomes (centrosome amplification) occur frequently in cancers, and are considered to be the major cause of chromosome instability, which accelerates acquisition of malignant phenotypes during tumor progression. Loss or mutational inactivation of p53 tumor suppressor protein, one of the most common mutations found in cancers, results in a high frequency of centrosome amplification in part via allowing the activation of the cyclin-dependent kinase (CDK) 2-cyclin E (as well as CDK2-cyclin A) which is a key factor for the initiation of centrosome duplication. In this review, the role of centrosome amplification in tumor progression, and mechanistic view of how centrosomes are amplified in cells through focusing on loss of p53 and aberrant activities of CDK2-cyclins will be discussed.
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PMID:P53, cyclin-dependent kinase and abnormal amplification of centrosomes. 1847 15

Abnormal amplification of centrosomes, which occurs frequently in cancers, leads to high frequencies of mitotic defect and chromosome segregation error, profoundly affecting the rate of tumor progression. Centrosome amplification results primarily from overduplication of centrosomes, and p53 is involved in the regulation of centrosome duplication partly through controlling the activity of cyclin-dependent kinase (CDK) 2-cyclin E, a kinase complex critical for the initiation of centrosome duplication. Thus, loss or mutational inactivation of p53 leads to an increased frequency of centrosome amplification. Moreover, the status of cyclin E greatly influences the frequency of centrosome amplification in cells lacking functional p53. Here, we dissected the roles of CDK2-associating cyclins, namely cyclins E and A, in centrosome amplification in the p53-negative cells. We found that loss of cyclin E was readily compensated by cyclin A for triggering the initiation of centrosome duplication, and thus the centrosome duplication kinetics was not significantly altered in cyclin E-deficient cells. It has been shown that cells lacking functional p53, when arrested in either early S-phase or late G(2) phase, continue to reduplicate centrosomes, resulting in centrosome amplification. In cells arrested in early S phase, cyclin E, but not cyclin A, is important in centrosome amplification, whereas in the absence of cyclin E, cyclin A is important for centrosome amplification. In late G(2)-arrested cells, cyclin A is important in centrosome amplification irrespective of the cyclin E status. These findings advance our understandings of the mechanisms underlying the numeral abnormality of centrosomes and consequential genomic instability associated with loss of p53 function and aberrant expression of cyclins E and A in cancer cells.
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PMID:Roles of cyclins A and E in induction of centrosome amplification in p53-compromised cells. 1849 Sep 19

The p16(INK4a)-Rb tumour suppressor pathway is required for the initiation and maintenance of cellular senescence, a state of permanent growth arrest that acts as a natural barrier against cancer progression. Senescence can be overcome if the pathway is not fully engaged, and this may occur when p16(INK4a) is inactivated. p16(INK4a) is frequently altered in human cancer and germline mutations affecting p16(INK4a) have been linked to melanoma susceptibility. To characterize the functions of melanoma-associated p16(INK4a) mutations, in terms of promoting proliferative arrest and initiating senescence, we utilized an inducible expression system in a melanoma cell model. We show that wild-type p16(INK4a) promotes rapid cell cycle arrest that leads to a senescence programme characterized by the appearance of chromatin foci, activation of acidic beta-galactosidase activity, p53 independence and Rb dependence. Accumulation of wild-type p16(INK4a) also promoted cell enlargement and extensive vacuolization independent of Rb status. In contrast, the highly penetrant p16(INK4a) variants, R24P and A36P failed to arrest cell proliferation and did not initiate senescence. We also show that overexpression of CDK4, or its homologue CDK6, but not the downstream kinase, CDK2, inhibited the ability of wild-type p16(INK4a) to promote cell cycle arrest and senescence. Our data provide the first evidence that p16(INK4a) can initiate a CDK4/6-dependent autonomous senescence programme that is disabled by inherited melanoma-associated mutations.
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PMID:p16INK4a-induced senescence is disabled by melanoma-associated mutations. 1884 95

Cyclin-dependent kinases (CDKs) play important roles in regulating cell cycle progression, and altered cell cycles resulting from over-expression or abnormal activation of CDKs observed in many human cancers. As a result, CDKs have become extensive studied targets for developing chemical inhibitors for cancer therapies; however, protein kinases share a highly conserved ATP binding pocket at which most chemical inhibitors bind, therefore, a major challenge in developing kinase inhibitors is achieving target selectivity. To identify cell growth inhibitors with potential applications in cancer therapy, we used an integrated approach that combines one-pot chemical synthesis in a combinatorial manner to generate diversified small molecules with new chemical scaffolds coupled with growth inhibition assay using developing zebrafish embryos. We report the successful identification of a novel lead compound that displays selective inhibitory effects on CDK2 activity, cancer cell proliferation, and tumor progression in vivo. Our approaches should have general applications in developing cell proliferation inhibitors using an efficient combinatorial chemical genetic method and integrated biological assays. The novel cell growth inhibitor we identified should have potential as a cancer therapeutic agent.
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PMID:Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays. 1919 8

Galectin-3, a beta-galactoside-binding protein, has been implicated in a variety of biological functions including cell proliferation, apoptosis, angiogenesis, tumor progression, and metastasis. The present study was undertaken to understand the role of galectin-3 in the progression of prostate cancer. Immunohistochemical analysis of galectin-3 expression revealed that galectin-3 was cleaved during the progression of prostate cancer. Galectin-3 knockdown by small interfering RNA (siRNA) was associated with reduced cell migration, invasion, cell proliferation, anchorage-independent colony formation, and tumor growth in the prostates of nude mice. Galectin-3 knockdown in human prostate cancer PC3 cells led to cell-cycle arrest at G(1) phase, up-regulation of nuclear p21, and hypophosphorylation of the retinoblastoma tumor suppressor protein (pRb), with no effect on cyclin D1, cyclin E, cyclin-dependent kinases (CDK2 and CDK4), and p27 protein expression levels. The data obtained here implicate galectin-3 in prostate cancer progression and suggest that galectin-3 may serve as both a diagnostic marker and therapeutic target for future disease treatments.
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PMID:Regulation of prostate cancer progression by galectin-3. 1928 70

MicroRNAs are noncoding, endogenous small RNAs that regulate target genes by cleavage of the targeted mRNA or translational repression. We investigated the microRNAome using 2-color microarrays in a highly invasive human breast cancer cell line, MDA-MB-231 (subline 4175) and a noninvasive breast epithelial cell line, MCF10A. We found 13 microRNAs that were up-regulated, and nine were down-regulated significantly in 4175 cells (p < 0.05, -fold change >2) compared with MCF10A cells. Interestingly, miR-27b and its putative target gene, ST14 (suppressor of tumorigenicity 14), had inverse expression pattern in breast cancer cells. The 3'-untranslated region of ST14 contains a regulatory element for miR-27b, and our luciferase experiments indicate that antisense miR-27b enhances ST14 expression in cancer cells. Furthermore, antagomir of miR-27b suppressed cell invasion in 4175 cells, whereas pre-miR-27b stimulated invasion in moderately invasive ZR75 breast cancer cells. In addition, ST14 reduces cell proliferation as well as cell migration and invasion. Analysis of human breast tumors revealed that miR-27b expression increases during cancer progression, paralleling a decrease in ST14 expression. Furthermore, our data indicate that ST14 inhibits cells from entering into S phase by up-regulating p27, which results in down-regulation of cyclin E-CDK2 complexes, suggesting ST14 reduces cell growth through its effects on cell cycle-related proteins. Introduction of miR-27b into ST14-expressing cells did not suppress the effect on cell growth. These findings suggest that ST14 plays an important role in several biological processes, and some effects are not completely dependent on miR-27b regulation.
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PMID:ST14 (suppression of tumorigenicity 14) gene is a target for miR-27b, and the inhibitory effect of ST14 on cell growth is independent of miR-27b regulation. 1954 20

Parathyroid hormone-related protein (PTHrP), a paraneoplastic protein expressed by two-thirds of human non-small cell lung cancers, has been reported to slow progression of lung carcinomas in mouse models and to lengthen survival of patients with lung cancer. This study investigated the effects of ectopic expression of PTHrP on proliferation and cell cycle progression of two human lung adenocarcinoma cell lines that are normally PTHrP negative. Stable transfection with PTHrP decreased H1944 cell DNA synthesis, measured by thymidine incorporation, bromodeoxyuridine uptake, and MTT proliferation assay. A substantial fraction of PTHrP-positive cells was arrested in or slowly progressing through G1. Cyclin D2 and cyclin A2 protein levels were 60-70% lower in PTHrP-expressing cells compared with control cells (P < 0.05, N = 3 independent clones per group), while expression of p27(Kip1), a cyclin-dependent kinase inhibitor, was increased by 35 +/- 9% (mean +/- SE, P < 0.05) in the presence of PTHrP. Expression of other cyclins, including cyclins D1 and D3, and cyclin-dependent kinases was unaffected by PTHrP. PTHrP did not alter the phosphorylation state of Rb, but decreased cyclin-dependent kinase (CDK) 2-cyclin A2 complex formation. Ectopic expression of PTHrP stimulated ERK phosphorylation. In MV522 cells, PTHrP had similar effects on DNA synthesis, cyclin A2 expression, pRb levels, CDK2-cyclin A2 association, and ERK activation. In summary, PTHrP appears to slow progression of lung cancer cells into S phase, possibly by decreasing activation of CDK2. Slower cancer cell proliferation could contribute to slower tumor progression and increased survival of patients with PTHrP-positive lung cancer.
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PMID:Cell cycle actions of parathyroid hormone-related protein in non-small cell lung carcinoma. 1963 68

The Ras/Raf/MEK/ERK signaling has been implicated in uncontrolled cell proliferation and tumor progression in pancreatic cancer. The purpose of this study is to evaluate the antitumor activity of MEK inhibitor U0126 in combination with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in pancreatic cancer cells. Western blotting showed that 17-AAG caused a 2- to 3-fold transient activation of MEK/ERK signaling in pancreatic cancer cells. The activation sustained for 6 h before phospho-ERK (p-ERK) destabilization. The selective MEK inhibitor U0126 completely abolished 17-AAG induced ERK1/2 activation and resulted in more than 80% of phospho-ERK degradation after only 15 min treatment. Moreover, U0126 had complementary effect on 17-AAG regulated oncogenic and cell cycle related proteins. Although 17-AAG downregulated cyclin D1, cyclin E, CDK4 and CDK6, it led to cyclin A and CDK2 accumulation, which was reversed by the addition of U0126. Antiproliferation assay showed that combination of U0126 and 17-AAG resulted in synergistic cytotoxic effect. More importantly, 17-AAG alone only exhibited moderate inhibition of cell migration in vitro, while addition of U0126 dramatically enhanced the inhibitory effect by 2- to 5-fold. Taken together, these data demonstrate that MEK inhibitor U0126 potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells. The combination of Hsp90 and MEK inhibition could provide a promising avenue for the treatment of pancreatic cancer.
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PMID:MEK inhibition potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells. 2066 73

bHLH/PAS proteins play important roles in tumor progression. Lost or reduced expression of single-minded homolog 2 (SIM) as well as aryl hydrocarbon receptor repressor (AHRR) has been observed in cancerous human tissues. Here, we investigated the role of aryl hydrocarbon receptor nuclear translocator (ARNT), another bHLH/PAS protein, in hepatocellular carcinoma (HCC). Using tissue microarray and immunohistochemistry, we found that intratumoral ARNT was inversely correlated with time to recurrence and overall survival of HCC patients after resection. Knockdown of ARNT in HepG2, HCCLM3 and HCCLM6 cells significantly shortened cell doubling time, increased S-phase cell populations and accelerated in vivo HCCLM6 growth and metastasis. After ARNT expression was rescued, prolonged cell doubling time and decreased S-phase cell populations were observed in HepG2, HCCLM3 and HCCLM6 cells. And, HCCLM6 growth and metastasis in vivo were remarkably inhibited. Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC. According to the results of immunoprecipitation assay, both ARNT/ARNT and ARNT/AHRR complexes were clearly formed in HCCLM6 xenograft with increased ARNT expression. In summary, ARNT is an important regulator of HCC growth and metastasis and could be a promising prognostic candidate in HCC patients.
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PMID:Aryl hydrocarbon receptor nuclear translocator is associated with tumor growth and progression of hepatocellular carcinoma. 2154 13


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