We propose that UGT2B28, UGT2B10, UGT2B11, Skp2, EZH2, MDM2, BIRC5 (Survivin), UBE2C, and Smads 1/5/8, which are all associated with the abovementioned key oncogenic pathways, may play critical roles in the putative oncogenic function of JAB1 in PCa.
Selectively blocking MDM2-mediated activity in combination with androgen/AR-targeted therapy may offer a novel strategy for eliminating AR<sup>-</sup> CSCs in addition to the bulk of AR<sup>+</sup> prostate cancer cells, decreasing metastatic tumor burden and inhibiting the emergence of therapeutic resistance.<b>Significance:</b> These findings provide a novel mechanistic aspect of prostate cancer cell stemness that advances our understanding of the diverse transcriptional activity that bypasses AR in contributing to therapeutic resistance, tumor progression, and metastasis.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/79/6/1124/F1.large.jpg.
Our present study provides compelling evidence that pharmacological activation of the p53 by blocking the MDM2-p53 interaction is a promising cancer therapeutic strategy and using RITA in combination with Cisplatin not only decrease the toxic effect of Cisplatin by decreasing its dose but also increasing the apoptotic effect, warrants clinical evaluation on both colon and prostate cancer.
As a result, the CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I axis was identified as a bottleneck in the miRNA-mediated gene expression regulatory network of PCa according to network topological analysis.
Mechanistically, GS25 directly bound to the RING domain of MDM2, disrupted MDM2-MDMX binding and induced MDM2 protein degradation, resulting in strong inhibition of prostate cancer cell growth and metastasis, independent of p53 and androgen receptor status.
As a novel tumor suppressor, miRNA-509-5p in prostate cancer HGC-27 cells can suppress MDM2 expression and inhibit cell proliferation, invasion, and migration.
The MDM2 and MDMX oncogenes are overexpressed in various types of human cancer and are highly associated with the initiation, progression, metastasis and chemotherapeutic resistance of these diseases, including prostate cancer.
Taken together, our study suggests that FOXQ1 regulates prostate cancer cell proliferation and apoptosis by regulating BCL11A/MDM2 expression and indicates that FOXQ1 may serve as a potential therapeutic target for prostate cancer.
These findings support MDM2 small molecule inhibitor therapy as a therapy intensification strategy to improve clinical outcomes in high-risk localized prostate cancer.
In this large population based case-control study, we genotyped MDM2 SNP55 in 10,779 Caucasian individuals, previously genotyped for SNP309 and SNP285, including cases of colon (n = 1,524), lung (n = 1,323), breast (n = 1,709) and prostate cancer (n = 2,488) and 3,735 non-cancer controls, as well as 299 healthy African-Americans.
Overall, there was no statistical association between MDM2 SNP309 and prostate cancer risk for the allele contrast, the GG genotype, the recessive genetic model, the dominant genetic model, and prostate cancer risk in all subjects (OR = 0.96, 95% CI 0.87-1.05, P = 0.36; OR = 0.93, 95% CI 0.75-1.15, P = 0.50; OR = 1.00, 95% CI 0.87-1.15, P = 0.99; OR = 0.93, 95% CI 0.80-1.07, P = 0.30), and between MDM2 SNP309 and bladder cancer risk (the allele contrast: OR = 1.06, 95% CI 0.89-1.27, P = 0.50; the GG genotype: OR = 1.12, 95% CI 0.79-1.61, P = 0.52; the dominant genetic model: OR = 1.03, 95% CI 0.83-1.28, P = 0.78; the recessive genetic model: OR = 1.12, 95% CI 0.84-1.49, P = 0.45).
Our findings suggest that miR-340 may function as a novel tumor suppressor in PCa through the MDM2-p53 pathway by directly targeting MDM2, which may be a promising miRNA-targeted therapy for PCa.
Finally, we demonstrate that the unrelated MDM2 antagonist Mi-63 also impinges upon AR signalling, supporting the concept of future treatment of prostate cancer with MDM2 antagonists.
We conclude, MDM4 SNP34091 status to be associated with reduced risk of breast cancer, in particular in individuals carrying the MDM2 SNP309GG genotype, but not to be associated with either lung-, colon- or prostate cancer.
The identification of the alternative reading frame protein (ARF) / murine double minute protein (MDM2) / p53 tumour suppressor pathway potentially involving the IL-6/STAT3 axis as a restricting factor in prostate cancer deficient in the tumour suppressor phosphatase and tensin homologue (PTEN) opened new avenues to currently available therapies.
The purpose of this study was to evaluate the relationship between single-nucleotide polymorphism (SNP) rs2228001 in xeroderma pigmentosum group C (XPC), SNP rs4073 in interleukin 8 (IL8), and SNP rs2279744 in mouse double minute 2 (MDM2) homolog gene with PCa susceptibility.
The cumulative positive rate of autoantibodies against seven selected TAAs (cyclin B1, survivin, p53, DFS70/LEDGFp75, RalA, MDM2, and NPM1) in PCa reached 80.5%, significantly higher than that in normal control sera.