Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Even if prognosis of epithelial ovarian cancer remains very bad, survival and response to treatment are variable according to the patients. Determination of new prognostic markers helps us to adapt therapeutics for each patient and is necessary for the elaboration and the interpretation of clinical research studies. Many prognostic factors related to the tumor, the patient or the treatment, have been evaluated. The goal of this work is to review these parameters. So far, the most powerful variables are volume of residual disease after cytoreductive surgery, FIGO tumor stage, histologic type and grade of differentiation. The progress and accessibility to novel technologies applied to biology will make possible in the future the assessment of new prognostic profiles-based on genetic and/or proteomic tumor characteristics. The future also relies on the identification of predictive factors of response to treatment, but force is to note that on the last hundred publications testing predictive factors (p53, HER2, Topo-2-alpha, BRCA...), none have modified today our clinical practices.
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PMID:[Prognostic and predictive factors in epithelial ovarian cancer]. 1935 17

The stress-activated kinase p38 plays key roles in tumor suppression and induction of tumor cell dormancy. However, the mechanisms behind these functions remain poorly understood. Using computational tools, we identified a transcription factor (TF) network regulated by p38alpha/beta and required for human squamous carcinoma cell quiescence in vivo. We found that p38 transcriptionally regulates a core network of 46 genes that includes 16 TFs. Activation of p38 induced the expression of the TFs p53 and BHLHB3, while inhibiting c-Jun and FoxM1 expression. Furthermore, induction of p53 by p38 was dependent on c-Jun down-regulation. Accordingly, RNAi down-regulation of BHLHB3 or p53 interrupted tumor cell quiescence, while down-regulation of c-Jun or FoxM1 or overexpression of BHLHB3 in malignant cells mimicked the onset of quiescence. Our results identify components of the regulatory mechanisms driving p38-induced cancer cell quiescence. These may regulate dormancy of residual disease that usually precedes the onset of metastasis in many cancers.
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PMID:Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence. 1958 93

PURPOSE To find out if TP53 functional status predicts response to neoadjuvant chemotherapy and thus may be helpful during treatment decision making of oral cavity squamous cell carcinoma (SCC) patients. PATIENTS AND METHODS We analyzed the predictive value of TP53 mutations and their functional status on the basis of the transactivation activity of p53 mutant proteins in 53 pretreatment biopsies of oral cavity SCC patients receiving primary cisplatin and fluorouracil chemotherapy followed by surgery. Results The surgical specimens showed that 15 patients (28%) achieved a pathologic complete remission (pCR) at both T and N sites, and 38 patients had residual tumor cells. Among the 53 pretreatment biopsies, 24 (45%) displayed TP53 mutations: 22 single-nucleotide substitutions and two deletions. According to functional status that could be determined only for the 22 substitutions, 21 mutations were nonfunctional and one was partially functional. TP53 mutation was found in four (27%) of 15 patients who achieved a pCR and in 20 (53%) of 38 nonresponder patients; the difference was not statistically significant (P = .12). In contrast, two (14%) of 14 cases with pCR carried a nonfunctional TP53 mutation, a frequency significantly less than that found in the nonresponders (19 [51%] of 37; P = .02). TP53 mutation predicted pCR in four (17%) of 24 patients and a nonfunctional mutation in only two (9%) of 22 patients. CONCLUSION The results indicate that the loss of function (transactivation activities) of p53 mutant proteins may predict a significant low pCR rate and suboptimal response to cisplatin-based neoadjuvant chemotherapy in patients with oral cavity SCC.
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PMID:TP53 mutations and pathologic complete response to neoadjuvant cisplatin and fluorouracil chemotherapy in resected oral cavity squamous cell carcinoma. 2004 71

Tumor-initiating cells (TICs) have been shown both experimentally and clinically to be resistant to radiation and chemotherapy, potentially resulting in residual disease that can lead to recurrence. In this study, we demonstrate that TICs isolated from p53 null mouse mammary tumors repair DNA damage following in vivo ionizing radiation more efficiently than the bulk of the tumor cells. Down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was observed both in fluorescence activated cell sorting (FACS)-isolated TICs as compared to non-TICs and in TIC-enriched mammospheres as compared to primary tumor cells depleted of TICs. This effect was accompanied by increased Akt signaling, as well as by the direct activation of the canonical Wnt/beta-catenin signaling pathway specifically within the TIC subpopulation by phosphorylation of beta-catenin on serine 552. Using limiting dilution transplantation performed on p53 null tumor cells transduced with Wnt reporter lentivirus, we demonstrated that FACS sorting of cells expressing TOP-eGFP resulted in a marked enrichment for TICs. Furthermore, FACS analysis demonstrated that cells with active Wnt signaling overlapped with the TIC subpopulation characterized previously using cell surface markers. Finally, pharmacological inhibition of the Akt pathway in both mammospheres and syngeneic mice bearing tumors was shown to inhibit canonical Wnt signaling as well as the repair of DNA damage selectively in TICs, sensitizing them to ionizing radiation treatment. Thus, these results suggest that pretreatment with Akt inhibitors before ionizing radiation treatment may be of potential therapeutic benefit to patients.
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PMID:Selective targeting of radiation-resistant tumor-initiating cells. 2013 17

The establishment and characterization of a new human endometrioid adenocarcinoma cell line (KOC-8e) derived from the malignant ascites is described. The original tumor at the initial operation showed positive in TPA, and SLX immunohistochemically. By contrast, recurred tumor showed positive for CA125, TPA, SLX, MUC-1, and p53. In addition, the heterotransplanted tumor showed positive for CA125, TPA, SLX, MUG-1, and p53. The DNA index was similar in the primary, recurred, and nude mouse tumor ranging between 1.93 and 2.05. The tumor growths were suppressed dose dependently by CDDP and CPT-11. CA125 showed useful as a tumor marker of this tumor, however, the nude mice had detectable tumor without elevation of CA125 after low dose application of CDDP and CPT-11. Thus, clinical determination of chemotherapeutic effect and residual tumor cannot be made only by CA125. KOC-8e cells could be useful to study histological analysis and chemosensitivity.
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PMID:Establishment and characterization of ovarian endometrioid adenocarcinoma cell line in nude mice and analyses of the immunohistochemical property among the original, recurred, and heterotransplanted tumor. 2153 77

One hundred and twenty patients with rectal carcinoma in the lower two-thirds of the rectum were treated with preoperative radiotherapy and radical surgery between October 1986 and March 1996. The expression of p53 was examined in 58 of these patients, all of whom had undergone surgery more than 5 years previously and whose prognosis had been recorded. Eighteen of 58 (31%) cases showed pS3 overexpression. Clinicopathological variables other than pathological T stage did not correlate with p53 expression. The proportion of residual tumor cells in p53 positive group was significantly higher than that in the negative group. Survival time was significantly shorter in p53 positive than in p53 negative patients (p = 0.0042). The proportion of cumulative local recurrence in the p53 negative group was 2.8%, while that of the p53 positive group was 43.2% (p = 0.01). The cumulative survival rate in the p53 negative group was 76.3%, while that in the p53 positive group was 24.4% (p = 0.04). The amount of p53 positive cells in both local and distant recurrence cases was significantly higher than that without recurrence (p < 0.0001, p = 0.0016) respectively. These results suggest that p53 overexpression might predict a poor outcome at the resection of the irradiated rectal carcinoma.
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PMID:A possible correlation between p53 overexpression and prognosis after radiotherapy combined surgery for rectal carcinoma. 2153 72

Retinoic acid therapy is nowadays an important component of treatment for residual disease of stage IV neuroblastoma after multimodal therapy. Nevertheless, arising resistance and treatment toxicity could represent relevant limiting factors. In the present study, we show that retinoic acid enhances the cytostatic and apoptogenic properties of the novel adamantyl retinoid ST1926 in a panel of neuroblastoma cells with different p53 status and caspase 8 expression, resulting in synergistic effects as assessed by Combination Index and Isobologram analysis. Under conditions where the two drugs alone produced no toxic effects, their combination resulted in enhanced G2-M arrest and sub-G1 population as shown by BrdU pulse-chase and labeling experiments. PARP cleavage, caspase 3, 8 and 9 activation and modulation of DR4 and FAS were indicative of enhanced apoptosis triggered by the co-incubation of the two drugs whereas neither ST1926-mediated genotoxic damage nor ATRA-differentiating effects were affected by the combined treatment. Caspase-3 and 8-mediated apoptosis appeared to play an important role in the drugs synergism. In fact, the addition of a pan-caspase inhibitor ZVAD-FMK reverted this effect in SK-N-DZ cells, and synergism was confined to limited drugs doses in HTLA cells not expressing caspase-8. Although not modulated, p53 appeared to enhance cells responsiveness to retinoid/ATRA combination. In vivo studies in the most sensitive neuroblastoma model SK-N-DZ, confirmed enhanced activity of the drugs combination vs single treatments. The study provides important lines of evidence that such a drugs combination could represent a less toxic and more effective approach for maintenance treatment in children with neuroblastoma.
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PMID:Enhanced cell cycle perturbation and apoptosis mediate the synergistic effects of ST1926 and ATRA in neuroblastoma preclinical models. 2163 25

Epithelial ovarian cancer (EOC) prognosis is associated with International Federation of Gynecology and Obstetrics (FIGO) staging, cancer cell classification, patient age, and residual tumor size. However, the molecular markers for predicting EOC prognosis remain to be explored. In this study, we investigated the expression of CD24, COX-2, and p53 in EOC, and their relationships to clinical prognosis. We found that the expression of CD24 was detected in the cell membrane in 90.6 percent (58/64) of EOC cases and in the cytoplasm in 54.7 percent (35/64) of EOC cases; 78.6 percent (11/14) cases of borderline tumors had CD24-positive staining in the cell membrane. All 9 cases of benign tumors were negative for CD24 staining. Expression of CD24 correlated with the nuclear expression of p53, but not with the expression of COX-2. Overexpression of CD24 is an independent factor associated with tumor metastasis, a low survival rate, and a short survival time. Our results suggest that CD24 may be a valuable molecular marker for predicting prognoses of patients with EOC.
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PMID:CD24, COX-2, and p53 in epithelial ovarian cancer and its clinical significance. 2265 75

Dysregulated signaling on the PI3-kinase/Akt cascade is reportedly associated with early stage and favorable prognosis in some kinds of malignancies including breast cancer, endometrial cancer, and colorectal cancer. PIK3CA, a catalytic subunit of PI3-kinase, is known to be activated in ovarian clear cell carcinoma (CCC), which is categorized as type I ovarian cancer. The aim of this study was to investigate the clinical significance of PIK3CA overexpression in the disease. We performed immunohistochemical analyses of PIK3CA, PTEN, p-Akt, p27 and p53 expressions in primary ovarian clear cell carcinomas from 62 Japanese patients. Genetic analyses of PIK3CA mutation and amplification were further conducted. PIK3CA was overexpressed in 45 tumors (73%), PTEN expression was negative in 3 (5%), and p53 was positive in 8 (13%). Overexpressed PIK3CA was found to be associated with p-Akt overexpression (P = .007). PIK3CA overexpression tended to be observed in more of stage I disease (73% versus 47%, P = .07) and was associated with absence of residual tumor at the initial surgery (96% versus 71%, P = .01). Furthermore, survival analyses revealed that PIK3CA overexpression correlated with improved overall survival (P = .03). Subsequent genetic analyses demonstrated that PIK3CA overexpression correlated with the presence of mutation or amplification of the PIK3CA gene in tumors (P = .009). Our observations suggest that the subgroup of ovarian clear cell carcinomas harboring activated PIK3CA seems to have better prognosis possibly due to more indolent biological property compared to tumors without PIK3CA activation. PIK3CA may serve as a biomarker for good prognosis and a possible therapeutic target in this lethal subtype of ovarian cancer.
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PMID:PIK3CA overexpression is a possible prognostic factor for favorable survival in ovarian clear cell carcinoma. 2295 7

We previously reported that cyclin E (CCNE1) amplification is strongly associated with resistance to treatment in serous ovarian cancer by high-resolution oligonucleotide copy number analysis. Dysregulation of cell cycle control has been implicated as the key event in human oncogenesis, and aberrant expression of G1-S phase-related genes in particular has been reported in epithelial ovarian cancer (EOC). Nevertheless, there are conflicting results concerning the prognostic values of these abnormalities in EOC. This study focused on advanced serous EOC cases and investigated the association between the expression of G1-S phase-regulatory proteins and clinicopathological parameters. The utility of these proteins as prognostic factors was assessed, and whether these targets reflect chemoresistance of advanced serous EOC was investigated. A total of 66 patients treated by primary surgery were evaluated in this study. Immunohistochemical analysis for cyclin D1, pRb, p16, p53, p27(Kip1), p21(Waf1/Cip1) and cyclin E was performed on formalin-fixed tissue sections collected from primary surgical specimens. The correlations between the expression of these proteins and the clinicopathological parameters, including progression-free survival (PFS), overall survival (OS) and chemosensitivity, were examined. Upon univariate analysis, overexpression of cyclin D1 was positively correlated with reduced PFS (p=0.00062) and OS (p=0.00037). Reduced expression of p27(Kip1) was associated with shorter OS (p=0.064). Upon multivariate analysis, overexpression of cyclin D1 (p=0.0019), reduced expression of p27(Kip1) (p=0.042) and residual tumor volume (p=0.0092) were identified as independent predictors of OS. Overexpression of cyclin D1 (p=0.011) as well as residual tumor volume (p=0.006) were significantly associated with first-line chemosensitivity. In advanced serous EOC, overexpression of cyclin D1 contributed largely to poor prognosis, and this may have been in part mediated by chemoresistance. Cyclin D1 is a possible target for overcoming the refractory nature of advanced serous EOC.
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PMID:Cyclin D1 predicts the prognosis of advanced serous ovarian cancer. 2297 90


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