Backgrounds-p53 is a tumor suppressor that prevents cancer onset and progression, and mutations in the p53 gene cause loss of the tumor suppressor function of the protein. The mutant p53 protein in tumor cells can form aggregates which contribute to the dominant-negative effect over the wild-type p53 protein, causing loss of p53 tumor suppression or gain of novel oncogenic functions. Mutations in p53 have been implicated in the pathogenesis of primary prostate cancer (PCa), and are often detected in recurrent and metastatic disease. Thus, targeting mutant p53 may constitute an alternative therapeutic strategy for advanced PCa for which there are no other viable options.Methods-In this study, we used immunoprecipitation, immunoflurorenscence, clonogic survival and cell proliferation assays, flow cytometric analysis and in vivo xenograft to investigate the biological effects of ReACp53, a cell-permeable peptide inhibitor of p53 aggregation, on mutant p53-carrying PCa cells.Results-Our results show that ReACp53 targets amyloid aggregates of mutant p53 protein and restores the p53 nuclear function as transcriptional factor, induces mitochondrial cell death and reduces DNA synthesis of mutant p53-carrying PCa cells; ReACp53 also inhibits xenograft tumor growth in vivo.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Current clinical diagnostic methods lack the specificity in detecting lung cancer patients. The issue is particularly critical for stage I and II patients. Considerable evidence showed microRNA plays a very important role in lung carcinogenesis. Here, we identified a panel of 41 miRNAs significantly elevated in patients with lung cancer, of which eight miRNAs were further validated in an independent sample cohort. Classification analysis using the panel of eight miRNAs generated a discriminatory power of 93.3 % sensitivity and 93.8 % specificity in separating non-small-cell lung cancer (NSCLC) patients from normal controls, indicating the miRNAs have a potential clinical utility in discriminating NSCLC. Interestingly, miR-1244 was found significantly elevated in the serum samples of lung cancer patients, and the test characteristics of the single miRNA were area under the curve (AUC) of 0.832 in NSCLC vs healthy controls, and 0.861 in NSCLC vs patients with unidentified pulmonary nodules. This is the first study showing serum miR-1244 could be a biomarker to screen lung cancer patients from the high-risk population.
Most gefitinib-treated patients with non-small cell lung cancer (NSCLC) would eventually develop resistance. Lysimachia capillipes (LC) capilliposide extracts from LC Hemsl. show both in vitro and in vivo anti-cancer effects. In this study we investigated whether LC capilliposide in combination with gefitinib could overcome the resistance of NSCLC cells to gefitinib and identified the signaling pathways involved. Treatment with LC capilliposide alone inhibited the growth of a panel of NSCLC cell lines (PC-9, H460, H1975, H1299 and PC-9-GR) sensitive or resistant to gefitinib with IC 50 values in the range of μg/mL. In the gefitinib-resistant PC-9-GR cells (which have a T790M EGFR mutation), LC capilliposide (at the IC 30 , i.e. 1.2 μg/mL) markedly enhanced the inhibitory effects of gefitinib with its IC 50 value being decreased from 6.80±1.00 to 0.77±0.12 μmol/L. By using the median effect analysis we showed that combination treatment of LC capilliposide and gefitinib could restore gefitinib sensitivity in PC-9-GR cells. Furthermore, LC capilliposide (1.2 μg/mL) significantly increased the apoptotic responses to gefitinib (0.77 μmol/L) in PC-9-GR cells, but did not affect gefitinibinduced G 0 /G 1 arrest. Moreover, LC capilliposide (1.2 μg/mL) in combination with gefitinib (0.77, 1.0 μmol/L) markedly decreased the phosphorylation of the EGFR downstream signaling molecule AKT, which neither LC capilliposide nor gefitinib alone affected. In PC-9-GR cells with siRNA knockdown of AKT, addition of LC capilliposide was unable to increase gefitinib sensitivity. In a PC-9-GR xenograft mouse model, combination treatment with LC capilliposide (15 mg·kg -1 ·d -1, ip) and gefitinib (50 mg·kg -1 ·d -1, ip) dramatically enhanced tumor growth suppression (with a TGI of 109.3%), compared with TGIs of 22.6% and 56.6%, respectively, in mice were treated with LC capilliposide or gefitinib alone. LC capilliposide can restore the cells' sensitivity to gefitinib through modulation of pAKT levels, suggesting that a combination of LC capilliposide and gefitinib may be a promising therapeutic strategy to overcome gefitinib resistance in NSCLCs with a T790M mutation.
G protein-coupled receptor, family C, group 5 member A (GPRC5A) is a retinoid-inducible protein, which has been characterized as a tumor-suppressor gene in lung cancer. The present study further examined GPRC5A expression in non-small cell lung cancer (NSCLC) for any association with the clinical features and treatment outcomes of patients with NSCLC. A total of 30 paired NSCLC tumor and adjacent normal tissues were analyzed for the detection of GPRC5A mRNA and protein using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, respectively. Immunohistochemistry was performed to determine the GPRC5A expression levels in 110 NSCLC and 60 para-tumor tissues. The results confirmed significantly lower expression levels of GPRC5A in NSCLC tumors compared with the corresponding noncancerous tissues (P<0.001). Lost GPRC5A expression was significantly associated with the tumor histological type (P=0.008), poor tumor differentiation (P<0.001) and tumor-node-metastasis (TNM) stage (P<0.001). Kaplan-Meier curve analysis revealed that patients with NSCLC with low GPRC5A expression tumors had a worse prognosis compared with those with high GPRC5A expression tumors (P=0.010). The results of multivariate Cox analysis further suggested that low GPRC5A expression was an independent prognostic factor for patients with NSCLC (P<0.001). The results of this study suggest GPRC5A expression has clinical potential as a prognostic biomarker for patients with NSCLC.
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