Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells.
In DU145 xenograft tumor models, SCP exerted much stronger antitumor effects than P16 or estramustine (the clinical drug for prostate cancer) but caused fewer toxic side-effects.
Besides, p16 methylation was not linked to clinical stage, prostate-specific antigen (PSA) level, and Gleason score (GS) of patients with PCa. p14 methylation was not correlated with PCa in tissue and urine samples.
It was previously identified that elevation of YAP in genomics of genetic engineered mouse (GEM) model of prostate cancer is associated with Pten/Trp53 inactivation and ARF elevation hypothesizing the essential crosstalk of AKT/mTOR/YAP with ARF in prostate cancer.
In order to clarify the prognostic role of p16 and to draw conclusions on interactions with key molecular features of prostate cancer, we studied p16 expression in a tissue microarray (TMA) with more than 12,400 prostate cancers and attached clinical, pathological, and molecular data such as ERG status and deletions of 3p13, 5q21, 6q15, and PTEN. p16 immunostaining was absent in non-neoplastic prostate cells but was found in 37 % of 9627 interpretable prostate cancers.
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.
RMP16 showed prolonged half-life, 13.11 hours in mice (half-lives of P16 and TNF α are 5.77 and 29.0 minutes, respectively), and obviously higher receptor selectivity for TNFRI than TNF α. RMP16 had significant inhibition effects for multiple tumor cells, especially prostate cancer Du145 cells, and human vascular endothelial cells but not for human mammary non-tumorigenic epithelial cells.
In this study, we further extend our studies by showing that miR-125b represses the protein product of the ink4a/ARF locus, p14(ARF), in two prostate cancer cell lines, LNCaP (wild type-p53) and 22Rv1 (both wild type and mutant p53), as well as in the PC-346C prostate cancer xenograft model that lentivirally overexpressed miR-125b.
Our data suggest that the CDKN2a locus is a switch in PCa with methylation of p16(INK4a) being a marker for more aggressive tumours of Gleason score 7b, but no association with BMI overexpression was observed.
Studies on Radiation Therapy Oncology Group tissue samples have identified aberrant expression of p53, MDM2 (an E3 ubiquitin ligase that targets p53 for proteosomal degradation), and p16 (an upstream regulator of retinoblastoma and hence E2F1 in prostate cancer); abnormal expression of these biomarkers has been associated with clinical outcome after radiotherapy ± androgen deprivation therapy.
The finding of hypermethylated p14ARF sequences merits attention because this may indicate an intraosseal neoplastic process and may corroborate the hypothesis of prostate cancer.
Some genes have been found altered in prostate cancer, such as PTEN, TP53, AR, RNASEL (HPC1), ELAC2 (HPC2), CDKN2A and MSR1 and those can be natural targets for new strategies of treatment.
We tested urine sediment DNA for aberrant methylation of nine gene promoters (p16INK4a, p14(ARF), MGMT, GSTP1, RARbeta2, CDH1 [E-cadherin], TIMP3, Rassf1A, and APC) from 52 patients with prostate cancer and 21 matched primary tumors by quantitative fluorogenic real-time polymerase chain reaction.
In the present study, we report that EGCG-induced apoptosis in human prostate carcinoma LNCaP cells is mediated via modulation of two related pathways: (a) stabilization of p53 by phosphorylation on critical serine residues and p14ARF-mediated downregulation of murine double minute 2(MDM2) protein, and (b) negative regulation of NF-kappaB activity, thereby decreasing the expression of the proapoptotic protein Bcl-2.
There was no statistically significant association of grade (P = 0.18) and stage (P = 1.00) of prostate cancer to the elevated p16 levels in the tumors.
As alterations in tumor-suppressor gene p16 are common in prostate cancer, one novel approach is gene therapy using a replication-deficient, E1/E3-deleted adenovirus type 5 containing a p16 under the control of a truncated Rous sarcoma virus promoter (AdRSVp16).
These data suggest that increased expression of p16 protein, but not CDK4 protein, may be involved in the development of prostate carcinoma and may represent an independent predictor of biochemical failure after radical prostatectomy.