Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the expression of members of the bcl-2 family in human breast cancer. The expression pattern of these genes in breast cancer tissue samples was compared with the expression pattern in normal breast epithelium. No marked difference with regard to bcl-2 and bcl-xL expression was observed between normal breast epithelium and cancer tissue. In contrast, bax-alpha, a splice variant of bax, which promotes apoptosis, is expressed in high amounts in normal breast epithelium, whereas only weak or no expression could be detected in 39 out of 40 cancer tissue samples examined so far. Of interest, downregulation of bax-alpha was found in different histological subtypes. Furthermore, we transfected bax-alpha into breast cancer cell lines under the control of a tetracycline-dependent expression system. We were able to demonstrate for the first time that induction of bax expression in breast cancer cell lines restores sensitivity towards both serum starvation and APO-I/Fas-triggered apoptosis and significantly reduces tumor growth in SCID mice. Therefore, we propose that dysregulation of apoptosis might contribute to the pathogenesis of breast cancer at least in part due to an imbalance between members of the bcl-2 gene family.
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PMID:Overexpression of the death-promoting gene bax-alpha which is downregulated in breast cancer restores sensitivity to different apoptotic stimuli and reduces tumor growth in SCID mice. 864 29

In a mouse model of multistage tumorigenesis of islet beta-cells, apoptosis was activated concomitant with T-antigen oncogene-induced cell proliferation, further increased in the angiogenic stage, and markedly reduced in solid tumors. Crosses to p53-null mice confirmed this stage-specific variation as a p53-independent apoptotic process. Several apoptosis regulators were expressed, of which bcl-xL was up-regulated in tumors. When overexpressed throughout the pathway, bcl-xL protected most oncogene-expressing cells from apoptosis, enhancing progression from angiogenic progenitor to tumor without affecting earlier transitions. Further, two classes of solid tumor are described, distinguished by size and apoptotic incidence, implicating apoptosis regulation in expansive tumor growth. Thus, down-modulation of apoptosis selectively contributes to late steps in a tumorigenesis pathway.
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PMID:The rise and fall of apoptosis during multistage tumorigenesis: down-modulation contributes to tumor progression from angiogenic progenitors. 880 6

The rate of cell loss owing to apoptosis is mediated by competitive dimerization with selective pairs of cell death antagonists (Bcl-2, Bcl-X(L)) and agonists (Bax, Bad). The aim of this study was to investigate which Bcl-2 family dimers had a critical factor in colorectal cancer. We analyzed the expression of Bcl-2, Bcl-X(L), Bax, and Bad in normal-appearing mucosa and colorectal tumor tissues by Western blotting after immunoprecipitation. Compared with the ratio of Bax-Bcl-2/total Bax in normal mucosa, the ratio was significantly reduced in tumors (p = 0.02). In this series, the low ratio of Bad-Bcl-2/total Bcl-2 was associated with advanced tumor stages (p = 0.02). A reduced heterodimerization of Bax with Bcl-2 may contribute to the development of colorectal cancer. The heterodimerization of Bad with Bcl-2 may be repressed in advanced tumor tissues, and may contribute to tumor growth in colorectal cancer.
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PMID:Heterodimerization of Bcl-2 and Bcl-X(L) with Bax and Bad in colorectal cancer. 1104 Nov 12

Apoptosis is cellular suicide, the functional opposite of mitosis. It may play an important role in tissue growth control and removal of damaged and premalignant cells. The fact that diverse chemotherapeutic agents induce apoptosis, while they engage different intracellular targets and cause DNA damage, raises a concern that tumors resistant to chemotherapy are unable to initiate the apoptotic process. The anti-apoptotic Bcl-2 family proteins, Bcl-2 and Bcl-X(L), play an important role in the regulation of apoptotic cell death. Bcl-2 and Bcl-X(L)have been reported to confer chemotherapy resistance in short-term survival assays in vitro. However, they failed to provide a long-term clonogenic survival advantage. Thus, the role of anti-apoptotic Bcl-2 and Bcl-X(L)on chemotherapy resistance in vivo remains unclear. In vivo, tumor cells receive survival signals from the extracellular microenvironment. Since the microenvironmental factors have been reported to modulate the expression and function of Bcl-2 family proteins, Bcl-2 and Bcl-X(L)might be associated with the chemotherapy resistance in vivo through the influence of these factors. Consistent with this hypothesis, several investigators have recently reported that the sensitivity to chemotherapy in in vitro clonogenic assays did not correlate with that in in vivo tumor models. The lack of microenvironmental factors might cause the discrepancy between in vitro clonogenic growth and in vivo tumor growth. These results suggest that Bcl-2 and Bcl-X(L)could contribute to chemotherapy resistance in vivo, along with already defined drug resistance mechanisms (i.e. P-glycoprotein, MRP). Therapies aimed at suppressing the expression and function of Bcl-2 and Bcl-X(L)or at intercepting microenvironmental factors might successfully overcome chemotherapy resistance. Copyright 2000 Harcourt Publishers Ltd.
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PMID:In vivo veritas: Bcl-2 and Bcl-X(L)mediate tumor cell resistance to chemotherapy. 1149 79

Epidermal growth factor receptor (EGFR) is up-regulated and contributes to the loss of growth control in squamous cell carcinoma of the head and neck (SCCHN). Previously, we reported an association between autocrine stimulation of EGFR and constitutive signal transducers and activators of transcription (STAT) 3 activation in SCCHN cells in vitro and in vivo. Here, we evaluated the role of activated STAT3 in tumor progression and EGFR-independent mitogenic signaling. We found that SCCHN cells stably transfected with a dominant active STAT3 construct expressed elevated levels of STAT3 target genes, including Bcl-X(L) and cyclin D1, and demonstrated increased proliferation in vitro and more rapid tumor growth rates in vivo. Cell cycle analysis demonstrated an increased proportion of STAT3 construct transfectants in G(2)-M. These findings provide evidence that constitutive STAT3 activation contributes to tumor growth in SCCHN, independent of the EGFR autocrine axis.
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PMID:STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo. 1219 74

Bik was initially identified as a BH3-domain-only protein that interacts with E1B 19K. Although systemically administered wild-type Bik significantly inhibited tumor growth and metastasis in an orthotopic nude mouse model, the proapoptotic potency of Bik can be modulated by posttranslational phosphorylation. Here, we found that Bik mutants, in which threonine 33 and/or serine 35 were changed to aspartic acid to mimic the phosphorylation at these two residues, enhanced their binding affinity with the antiapoptotic proteins Bcl-X(L) and Bcl-2 and were more potent than wild-type Bik in inducing apoptosis and inhibiting cell proliferation in various human cancer cells. Bik mutants also suppressed tumorigenicity and tumor-taking rate in a mouse ex vivo model. Moreover, Bik mutant-liposome complexes inhibited tumor growth and prolonged life span more effectively than the wild-type Bik-liposome complex in an in vivo orthotopic animal model. Thus, our results demonstrate that Bik mutant genes, more potent than wild-type Bik, induce cell death and suggest that their inhibition on the growth of various cancers should be explored further.
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PMID:Enhancement of Bik antitumor effect by Bik mutants. 1463 80

Neuroblastoma is a pediatric tumor accounting for 15% of childhood cancer deaths and has a poor prognosis in children >1 year of age. We investigated the ability of apigenin, a nonmutagenic dietary flavonoid that has been shown to have antitumor effects in various tumor cell lines, to inhibit growth and induce apoptosis of the human neuroblastoma cell lines NUB-7, LAN-5, and SK-N-BE(2). Apigenin inhibited colony-forming ability and survival, and induced apoptosis of NUB-7 and LAN-5 cells. The presence of the C2-C3 double bond and the 4'-OH group on the flavonoid structure correlated with the growth-inhibitory potential of apigenin. Furthermore, apigenin inhibited NUB-7 xenograft tumor growth in anonobese diabetic/severe combined immunodeficiency mouse model, likely by inducing apoptosis. Apigenin did not inhibit survival of primary sympathetic neurons, suggesting that it is not toxic to nontransformed cells. The mechanism of action of apigenin seems to involve p53, as it increased the levels of p53 and the p53-induced gene products p21WAF1/CIP1 and Bax. Furthermore, apigenin (15-60 micromol/L) induced cell death and apoptosis of neuroblastoma cells expressing wild-type but not mutant p53. Apigenin increased caspase-3 activity and PARP cleavage, and Z-VAD-FMK, a broad-spectrum caspase-3 inhibitor, rescued NUB-7 cells from apigenin-mediated apoptosis indicating that apigenin induced apoptosis in acaspase-dependent manner. Overexpression of Bcl-X(L) rescued NUB-7 from apigenin-induced cell death, suggesting that Bax activity is important for the action of apigenin. Apigenin is thus a candidate therapeutic for neuroblastoma that likely acts by regulating a p53-Bax-caspase-3 apoptotic pathway.
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PMID:Induction of caspase-dependent, p53-mediated apoptosis by apigenin in human neuroblastoma. 1565 48

Overexpression of Bcl-2/Bcl-X(L) protein has been observed in more than 80% of B-cell lymphomas. Diffuse large cell lymphoma (DLCL) is the most common subtype of non-Hodgkin's lymphoma. (-)-Gossypol, a natural product isolated from cottonseeds, was discovered as a potent small-molecule inhibitor of Bcl-2 and Bcl-X(L) proteins, with a Ki value in the nanomole per liter range for both. In vitro, (-)-gossypol showed significant growth inhibition effect against WSU-DLCL2 lymphoma cell line and fresh cells obtained from a lymphoma patient with no effect on normal peripheral blood lymphocytes. As expected (-)-gossypol induced complete cytochrome c release from mitochondria, increased caspases-3 and -9 activity, and caused apoptotic death without affecting protein levels of Bcl-2, Bcl-X(L), Bax, and Bak. The addition of cyclophosphamide-Adriamycin-vincristine-prednisolone (CHOP) regimen to lymphoma cells preexposed to (-)-gossypol enhanced killing significantly. The maximum tolerated dose of (-)-gossypol in severe combined immunodeficient (SCID) mice was 40 mg/kg for three i.v. injections when given alone and 20 mg/kg x 3 when given in combination with CHOP. Using WSU-DLCL2-SCID mouse xenograft model, the tumor growth inhibition, the tumor growth delay, and the log10 kill of mice treated with (-)-gossypol + CHOP were better than CHOP or (-)-gossypol alone. We conclude that adding Bcl-2/Bcl-X(L) small-molecule inhibitor to standard chemotherapy may prove an effective strategy in lymphoma therapy.
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PMID:Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-X(L) [(-)-gossypol] against diffuse large cell lymphoma. 1565 49

Farnesyltransferase inhibitor (FTI) acts on ras, which can ultimately enhance radiosensitivity. The objective of this study was to explore whether FTI could potentiate the antitumor efficacy of radiation in vivo, particularly in radio-resistant hepatocarcinomas (HCa-I) syngeneic to C3H/HeJ mice. The presence of ras mutations was examined by PCR and DNA sequencing. C3H/HeJ mice, bearing HCa-I, were treated with FTI, LB42907, and 25 Gy radiation. FTI was orally administered, 60 mg/kg, twice daily for 30 days. The expression of regulating molecules was analyzed by Western blotting for p53, p21(WAF1/CIP1), and the Bcl-2 family, such as Bcl-2, Bax, and Bcl-X(L/s). In HCa-I, no ras mutations were detected. Downregulation of ras by FTI was most prominent at 4 h after treatment. In a tumor growth delay assay, FTI increased the effect of the tumor's radioresponse, with an enhancement factor of 1.32. Combined irradiation and FTI increased radiation-induced apoptosis; the peak apoptotic index was 3.6% with irradiation alone and with the drug alone but 7.1% in the combined treatment group. The analysis of apoptosis-regulating molecules by Western blotting showed upregulation of p53 and p21(WAF1/CIP1) in the combined treatment group compared with those in either of the single treatment groups, but the Bcl-2 family remained unchanged. FTI, in combination with radiation therapy, may have potential benefits in cancer treatment even if there are no ras mutations. FTI could inhibit ras activity but may also affect any protein that requires farnesylation for its activity.
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PMID:Enhancement of tumor response by farnesyltransferase inhibitor in C3H/HeJ hepatocarcinoma. 1565 85

The suppressors of cytokine signaling (SOCS) are inhibitors of cytokine signaling that function via the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Recently, methylation of SOCS-1 and SOCS-3 has been implicated in the tumorigenesis of liver and lung cancer. This study was performed to elucidate the role of SOCS-1 and SOCS-3 in squamous cell carcinoma of the head and neck (HNSCC) and its precursor lesions. HNSCC of 94 patients and corresponding normal mucosa, lymph node metastases as well as 16 high- and 21 low-grade squamous cell dysplasias were studied by using methylation-specific PCR (MSP) for the SOCS-1 and SOCS-3 promoter after microdissection. The presence of SOCS-3 mRNA transcripts was confirmed by semiquantitative real-time PCR, and the SOCS-3 protein was analysed immunohistochemically. SOCS-3 hypermethylation was found in 85/94 HNSCC (90%) and in 10/16 high-grade and 9/21 low-grade dysplasias (63 and 43%, respectively). SOCS-1 promoter hypermethylation was detected in 10/94 HNSCC samples (11%) and in 2/16 high-grade and 1/21 low-grade dysplasias (13 and 5%, respectively). Lymph node metastases exhibited an identical methylation status as the primary tumors. Methylation of the SOCS-3 promoter correlated with downregulation of SOCS-3 transcripts and protein expression in these tumors and various cell lines. In the cell lines tested, SOCS-3 and SOCS-1 transcripts increased upon treatment with the demethylation compound 5-aza-2-deoxycytidine (5-AZA-DC). Overexpression of wild-type SOCS-3 in carcinoma cells with methylated SOCS-3 resulted in the induction of apoptosis and growth suppression as well as downregulation of STAT3, bcl-2 as well as bcl-xL. Our data suggest that promoter methylation and subsequent transcript downregulation of SOCS-3 transcripts and, to a much lesser extent, SOCS-1 are involved in the multistep carcinogenesis of HNSCC. During its involvement in tumor growth, restoration of SOCS-3 may hold treatment potential for HNSCC.
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PMID:SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition. 1600 69


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