Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cyclin-dependent kinase (CDK) inhibitor p21(Cip1/Waf1) plays an essential role in the control of cell proliferation by modulating the activity of cyclin/CDK complexes in response to various intracellular or extracellular signals. Small variations in p21 expression levels may determine whether it acts as an inhibitor or an assembly factor for cyclin/CDK complexes. It is therefore critical to better characterize the mechanisms regulating p21 abundance. Here, we show, using a tetracycline-regulated system in p53-deficient DLD-1 human colon cancer cells, that p21 protein levels and stability are regulated by the proteasome-dependent degradation pathway and by association with its partners, CDKs and PCNA. A p21 mutant deficient for interaction with CDKs, p21CDK-, displayed an enhanced stability and greatly reduced sensitivity to proteasome-mediated proteolysis, indicating that association with cyclin/CDK complexes may trigger p21 degradation. In contrast, a p21 mutant impaired in the interaction with PCNA, p21PCNA-, exhibited a decreased stability, suggesting that association with PCNA protects p21 from proteasome-dependent degradation. Furthermore, the abundance of p21 itself, in addition to protein-protein interactions, may also modulate p21 stability since we found that high levels of p21 expression overcome proteasome-dependent regulation of p21 accumulation.
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PMID:Interaction with cyclin-dependent kinases and PCNA modulates proteasome-dependent degradation of p21. 982 54

Solid tumors commonly contain regions with glucose-starved and hypoxic conditions. Tumor cells under the adverse conditions can survive through the stress response, such as cell cycle arrest. In this study, we found that the stress conditions stimulated nuclear accumulation of proteasomes, large multicatalytic protease complexes, in human colon cancer HT-29 cells. The nuclear proteasome levels both in amount and in activity were increased approximately 4 and 2 times by glucose starvation and hypoxia, respectively. No changes were detected in the total expression levels of proteasome. The nuclear proteasome accumulation was also observed in ovarian cancer A2780 cells under glucose starvation, suggesting that this response was regardless of the origin of cancer cells. Our results indicate that the nuclear proteasome distribution is enhanced by glucose starvation and hypoxia, and suggest that the proteolysis by proteasome in the nucleus may play roles in the stress response of solid tumor cells.
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PMID:Glucose starvation and hypoxia induce nuclear accumulation of proteasome in cancer cells. 1032 7

Signaling by members of the Src family of protein tyrosine kinases, such as Src and Fyn, is important in many biological responses, including gene transcription, cell-cycle progression, and cell adhesion and spreading [1] [2]. Unregulated Src kinase activity has been implicated in the progression of colon cancer and transformation of cultured cells [3] [4] [5] [6]. Thus, precise regulation of Src activity is critical for normal cell growth. Src kinase activity is downregulated by the carboxy-terminal Src kinase (Csk), a tyrosine kinase that phosphorylates a conserved tyrosine residue in the carboxy-terminal tail of Src [7] [8]. When phosphorylated, this tyrosine residue mediates an intramolecular interaction that results in a 'closed' or inactive conformation [1] [2] [9] [10]. Here, we report that loss of csk resulted in a reduction in the abundance of the Src and Fyn proteins, which could be restored by reintroducing catalytically active Csk. The effect of Csk on Src expression was not due to an increase in Src message, but to stabilization of the Src protein. Inhibition of proteasome activity also increased the level of Src protein in csk-deficient cells. Src was found to be ubiquitinated, and activation of Src increased the extent of polyubiquitination. Thus, ubiquitin-proteasome-dependent degradation represents an additional mechanism by which active Src can be downregulated.
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PMID:Ubiquitin-dependent degradation of active Src. 1050 17

Colon carcinoma and melanoma cells containing either a deletion of the adenomatous polyposis coli tumor suppressor protein (APC) or mutation of the site in beta-catenin phosphorylated by glycogen synthase kinase-3beta (GSK-3beta) display elevated levels of detergent-soluble beta-catenin due to insensitivity of the cytosolic protein to proteasome-dependent degradation. In this study, we have examined the effect of beta-catenin mutation (S37F) or APC loss on the proteasome sensitivity of additional subcellular beta-catenin pools in melanoma cells. In contrast to detergent-soluble beta-catenin, the detergent-insoluble protein remains proteasome-sensitive irrespective of S37F mutation or APC status. This insoluble component appears associated primarily with nuclear cytoskeletal elements. In addition, DNase I treatment solubilized a portion of detergent-insoluble beta-catenin, suggesting that this fraction also contains chromatin-associated protein, and correlating with a proteasome-sensitive elevation in beta-catenin-stimulated reporter activity. Since the detergent-insoluble nuclear component of beta-catenin displays GSK-3beta- and APC-independent proteasome sensitivity, distinct from the soluble nuclear and cytosolic pools of this protein, regulation of beta-catenin proteasome sensitivity and the contribution of this process to beta-catenin function may be more complex than previously appreciated.
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PMID:Nuclear beta-catenin displays GSK-3beta- and APC-independent proteasome sensitivity in melanoma cells. 1069 68

Physiological cell conditions, such as glucose deprivation and hypoxia, play a role in developing drug resistance in solid tumors. These tumor-specific conditions cause decreased expression of DNA topoisomerase IIalpha (topo IIalpha), rendering cells resistant to topo II-targeted drugs, such as etoposide and doxorubicin. We show here that inhibition of proteasome attenuated drug resistance by inhibiting topo IIalpha depletion induced by glucose starvation and hypoxia. topo IIalpha restoration was seen only at the protein levels, indicating that the topo IIalpha protein depletion occurred through a proteasome-mediated degradation mechanism. The stress-induced etoposide resistance was effectively prevented in vitro by the proteasome inhibitor lactacystin in both intrinsically resistant and sensitive tumor cells (colon cancer HT-29 and ovarian cancer A2780 cells, respectively). Furthermore, lactacystin effectively enhanced the antitumor activity of etoposide in the refractory HT-29 xenograft. These results indicate that lactacystin could serve as a new therapeutic agent to circumvent resistance to topo II-targeted chemotherapy in solid tumors.
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PMID:Proteasome inhibition circumvents solid tumor resistance to topoisomerase II-directed drugs. 1081 Nov 20

In this study, we explored what effect inhibitors of the 26S proteasome have on cell cycle distribution and induction of apoptosis in human skin fibroblasts and colon cancer cells differing in their p53 status. We found that proteasome inhibition resulted in nuclear accumulation of p53. This was surprising because it is thought that the degradation of p53 is mediated by cytoplasmic 26S proteasomes. Nuclear accumulation of p53 was accompanied by the induction of both p21WAF1 mRNA and protein as well as a decrease in cells entering S phase. Interestingly, cells with compromised p53 function showed a marked increase in the proportion of cells in the G2-M phase of the cell cycle and an attenuated induction of apoptosis after proteasome inhibition. Taken together, our results suggest that proteasome inhibition results in nuclear accumulation of p53 and a p53-stimulated induction of both G1 arrest and apoptosis.
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PMID:Role of p53 in cell cycle regulation and apoptosis following exposure to proteasome inhibitors. 1084 24

We have previously shown that Epstein-Barr virus (EBV)-encoded EBNA-5 is localized to PML bodies (PODs) in EBV-immortalized lymphoblastoid cell lines (LCLs). Here we have extended our study of the subnuclear localization of EBNA-5 and found a strict co-localization with PML in LCLs and in BL lines with an immunoblastic, LCL-like phenotype. Moreover, GFP-EBNA-5 accumulated in PML bodies upon transfection into LCLs. In contrast, transfection of cell lines of non-immunoblastic origin with an EBNA-5 expression construct showed preferential localization of the protein to the nucleoplasm. Since PML is involved in proteasome-dependent protein degradation, we investigated the total levels and sub-cellular localization of EBNA-5 upon inhibition of proteasome activity. We found that a proteasome inhibitor, MG132, induced the translocation of both endogenous and transfected EBNA-5 to the nucleoli in every cell line tested. The total EBNA-5 protein levels were not affected by the proteasomal block. EBNA-5 forms complexes with heat shock protein Hsp70. The proteasome inhibitor induced a rise in total levels of Hsp70 and dramatically changed its homogeneous nuclear and cytoplasmic distribution into nucleolar and cytoplasmic. This effect was EBNA-5-independent. The nucleolar localization of Hsp70 was enhanced by the presence of EBNA-5, however. EBNA-5 also enhanced the nucleolar translocation of a mutant p53 in a colon cancer line, SW480, treated with MG132. The coordinated changes in EBNA-5 and Hsp70 localization and the effect of EBNA-5 on mutant p53 distribution upon MG132 treatment might reflect the involvement of EBNA-5 in the regulation of intracellular protein trafficking associated with the proteasome-mediated degradation.
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PMID:Proteasome inhibitor induces nucleolar translocation of Epstein-Barr virus-encoded EBNA-5. 1116 Dec 73

A bicyclic hexapeptide, RA-VII or O-methyl deoxybouvardin, isolated from Rubia cordifolia, is known to inhibit protein biosynthesis in vitro and in vivo. We here demonstrate that the treatment of human colon cancer DLD-1 cells with RA-VII induces cell growth inhibition associated with a partial G1 arrest and a rapid decrease (below 2 h) in the level of cyclin D1 protein. Since cycloheximide, another protein synthesis inhibitor, neither decreased the amount of cyclin D1 in the cells nor arrested cells in G1 phase, it is unlikely that this RA-VII-induced reduction of cyclin D1 was fully dependent on its direct inhibitory effect of protein synthesis. Northern blot analysis revealed that RA-VII did not affect the level of cyclin D1 mRNA. Meanwhile, pre-treatment of cells with lactacystin, a proteasome inhibitor, abolished the RA-VII-induced decrease in cyclin D1. Moreover, RA-VII still decreased cyclin D1 protein in the presence of cycloheximide. These results indicate that the RA-VII-induced cyclin D1 decrease depends on cyclin D1 degradation via the ubiquitin-proteasome pathway and does not require additional protein synthesis. RA-VII might actively proceed the degradation process of cyclin D1 via the ubiquitin-proteasome pathway in DLD-1 cells.
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PMID:Antitumor bicyclic hexapeptide RA-VII modulates cyclin D1 protein level. 1139 71

As a single agent, gemcitabine (2',2'-difluorodeoxycytidine) has shown minimal activity against gastrointestinal malignancies with only a modest improvement in survival in patients with pancreatic cancer. Recently, gemcitabine resistance has been associated with the up-regulation of mRNA and protein levels of the ribonucleotide reductase M2 subunit (RR-M2), a rate-limiting enzyme in DNA synthesis that is cell cycle regulated. In this study we show that flavopiridol, a cyclin-dependent kinase inhibitor, enhances the induction of apoptosis by gemcitabine in human pancreatic, gastric, and colon cancer cell lines. As determined by quantitative fluorescence microscopy, flavopiridol enhanced gemcitabine-induced apoptosis 10-15-fold in all of the cell lines tested in a sequence-dependent manner. This was confirmed by poly(ADP-ribose) polymerase cleavage and mitochondrial cytochrome c release. Colony formation assays confirmed the apoptotic rates, showing complete suppression of colony formation only after exposure to sequential treatment of G(24)-->F(24). This is associated with suppression of the RR-M2 protein. This appears to be related to down-regulation of E2F-1, a transcription factor that regulates RR-M2 transcription and hypophosphorylation of pRb. The proteasome inhibitor PS-341 could restore the protein levels of E2F-1 in G(24)-->F(24) treatment indicating that E2F-1 down-regulation is attributable to its increased degradation via ubiquitin-proteasome pathway. This also resulted in restoration of RR-M2 mRNA and protein. These results indicate that flavopiridol in gemcitabine-treated cells inhibits parts of the machinery necessary for the transcription induction of RR-M2. Thus, combining flavopiridol with gemcitabine may provide an important and novel new means of enhancing the efficacy of gemcitabine in the treatment of gastrointestinal cancers.
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PMID:Flavopiridol increases sensitization to gemcitabine in human gastrointestinal cancer cell lines and correlates with down-regulation of ribonucleotide reductase M2 subunit. 1148 36

Apoptosis is a morphologically distinct form of programmed cell death that plays a major role in cancer treatments. This cellular suicide program is known to be regulated by many different signals from both intracellular and extracellular stimuli. Here we report that p53 suppressed expression of the cellular FLICE-inhibitory protein (FLIP) that potentially blocks apoptotic signaling in human colon cancer cell lines expressing mutated and wild-type p53. In contrast, the expression of the death receptor KILLER/DR5 (TRAIL-R2) had no effect on FLIP expression, although exogenous p53 is known to induce KILLER/DR5 expression. In line with these observations, FLIP-negative cancer cells were sensitive to both p53- and KILLER/DR5-mediated apoptosis, whereas cells containing high levels of FLIP underwent apoptotic cell death when triggered by ectopic p53 expression but not by KILLER/DR5 expression. Treating the cells with a specific inhibitor of the proteasome inhibited the decrease of FLIP by p53, suggesting that p53 enhances the degradation of FLIP via a ubiquitin-proteasome pathway. Thus, the data indicate that p53-mediated downregulation of FLIP may explain the potent sensitization of human cancer cells to the apoptotic suicide program induced by wild-type p53 gene transfer.
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PMID:Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells. 1152 13


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