Impact of vitamin D metabolism on clinical epigenetics

The bioactive vitamin D (VD) metabolite, 1,25-dihydroxyvitamin D3 regulates essential pathways of cellular metabolism and differentiation via its nuclear receptor (VDR). Molecular mechanisms which are known to play key roles in aging and cancer are mediated by complex processes involving epigenetic mechanisms contributing to efficiency of VD-activating CYP27A1 and CYP27B1 or inactivating CYP24 enzymes as well as VDR which binds to specific genomic sequences (VD response elements or VDREs). Activity of VDR can be modulated epigenetically by histone acetylation. It co-operates with other nuclear receptors which are influenced by histone acetyl transferases (HATs) as well as several types of histone deacetylases (HDACs). HDAC inhibitors (HDACi) and/or demethylating drugs may contribute to normalization of VD metabolism. Studies link VD signaling through the VDR directly to distinct molecular mechanisms of both HAT activity and the sirtuin class of HDACs (SIRT1) as well as the forkhead transcription factors thus contributing to elucidate complex epigenetic mechanisms for cancer preventive actions of VD

Etude du role du gene myc et d'autres oncogenes dans la croissance et la differenciation cellulaire in vitro

SIGLECNRS T 57019 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Molecular cloning of infectious viral DNA from ecotropic neurotropic wild mouse retrovirus.

Among a mixture of amphotropic and ecotropic murine leukemia viruses (MuLVs) isolated from paralyzed wild mice, only N-tropic ecotropic MuLV, cloned by cell culture techniques, has been shown to induce paralysis after reinjection into susceptible mice (M. B. Gardner, Curr. Top. Microbiol. Immunol. 79:215-239, 1978). The viral DNA genome of one of these neurotropic MuLVs (Cas-Br-E) has been cloned in Charon 21A at the SalI site. One clone, designated NE-8, was studied in more detail. A restriction endonuclease map of this cloned DNA was derived. Cloned viral DNA microinjected into NIH 3T3 cells produced infectious MuLV which was characterized as XC+, ecotropic, and N-tropic. The virus that was recovered after the microinjection of NE-8 DNA was also injected into susceptible SIM.S and NIH Swiss mice and was found to induce lower limb paralysis in these animals. These results make it highly unlikely that other agents (which might have escaped detection and separation from ecotropic MuLV by the techniques previously used) play a role in the etiology of this disease and clearly indicate that the ecotropic MuLV genome harbors sequences responsible for this paralysis. The availability of this clone DNA would now allow us to map these sequences on the genome

Abnormal capacity to induce cholesterol efflux and a new LpA-I pre-beta particle in type 2 diabetic patients.

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Cross Modulation between the Androgen Receptor Axis and Protocadherin-PC in Mediating Neuroendocrine Transdifferentiation and Therapeutic Resistance of Prostate Cancer

Castration-resistant prostate cancers (CRPCs) that relapse after androgen deprivation therapies (ADTs) are responsible for the majority of mortalities from prostate cancer (PCa). While mechanisms enabling recurrent activity of androgen receptor (AR) are certainly involved in the development of CRPC, there may be factors that contribute to the process including acquired neuroendocrine (NE) cell-like behaviors working through alternate (non-AR) cell signaling systems or AR-dependent mechanisms. In this study, we explore the potential relationship between the AR axis and a novel putative marker of NE differentiation, the human male protocadherin-PC (PCDH-PC), in vitro and in human situations. We found evidence for an NE transdifferentiation process and PCDH-PC expression as an early-onset adaptive mechanism following ADT and elucidate AR as a key regulator of PCDH-PC expression. PCDH-PC overexpression, in turn, attenuates the ligand-dependent activity of the AR, enabling certain prostate tumor clones to assume a more NE phenotype and promoting their survival under diverse stress conditions. Acquisition of an NE phenotype by PCa cells positively correlated with resistance to cytotoxic agents including docetaxel, a taxane chemotherapy approved for the treatment of patients with metastatic CRPC. Furthermore, knockdown of PCDH-PC in cells that have undergone an NE transdifferentiation partially sensitized cells to docetaxel. Together, these results reveal a reciprocal regulation between the AR axis and PCDH-PC signals, observed both in vitro and in vivo, with potential implications in coordinating NE transdifferentiation processes and progression of PCa toward hormonal and chemoresistance

Cross modulation between the androgen receptor axis and protocadherin-PC in mediating neuroendocrine transdifferentiation and therapeutic resistance of prostate cancer.: PCDH-PC/AR cross-talk in driving NE differentiation

International audienceCastration-resistant prostate cancers (CRPCs) that relapse after androgen deprivation therapies (ADTs) are responsible for the majority of mortalities from prostate cancer (PCa). While mechanisms enabling recurrent activity of androgen receptor (AR) are certainly involved in the development of CRPC, there may be factors that contribute to the process including acquired neuroendocrine (NE) cell-like behaviors working through alternate (non-AR) cell signaling systems or AR-dependent mechanisms. In this study, we explore the potential relationship between the AR axis and a novel putative marker of NE differentiation, the human male protocadherin-PC (PCDH-PC), in vitro and in human situations. We found evidence for an NE transdifferentiation process and PCDH-PC expression as an early-onset adaptive mechanism following ADT and elucidate AR as a key regulator of PCDH-PC expression. PCDH-PC overexpression, in turn, attenuates the ligand-dependent activity of the AR, enabling certain prostate tumor clones to assume a more NE phenotype and promoting their survival under diverse stress conditions. Acquisition of an NE phenotype by PCa cells positively correlated with resistance to cytotoxic agents including docetaxel, a taxane chemotherapy approved for the treatment of patients with metastatic CRPC. Furthermore, knockdown of PCDH-PC in cells that have undergone an NE transdifferentiation partially sensitized cells to docetaxel. Together, these results reveal a reciprocal regulation between the AR axis and PCDH-PC signals, observed both in vitro and in vivo, with potential implications in coordinating NE transdifferentiation processes and progression of PCa toward hormonal and chemoresistance

Oncologic outcome after extraperitoneal laparoscopic radical prostatectomy: midterm follow-up of 1115 procedures.

International audienceBACKGROUND: Although the first laparoscopic radical prostatectomy was performed in 1997, few midterm oncologic data have been published for the extraperitoneal procedure. OBJECTIVE: To determine the oncologic outcome of extraperitoneal laparoscopic radical prostatectomy (ELRP). DESIGN, SETTING, AND PARTICIPANTS: From 2000 to 2007, 1115 consecutive patients underwent ELRP for a localized prostate cancer at our department. Follow-up was scheduled and standardized for all patients and recorded into a prospective database. Median postoperative follow-up was 35.6 mo. INTERVENTION: All ELRP were performed by three surgeons at the Department of Urology, Hospital Henri Mondor, Créteil, France. MEASUREMENTS: Biochemical recurrence was defined by prostate-specific antigen level > or =0.2 ng/ml. RESULTS AND LIMITATIONS: In pN0/pNx cancers, postoperative stage was pT2 in 664 patients (59.5%), pT3 in 350 patients (31.4%), and pT4 in 77 patients (6.9%). Positive lymph nodes were reported in 24 patients (2.2%). Margins were positive in 16.1% and 34.6% of pT2 and pT3 cancers, respectively. Final Gleason score was 7 in 126 men (11.3%). Overall prostate-specific antigen (PSA) recurrence-free survival was 83% at 5 yr. The 5-yr progression-free survival rates were 93.4% for pT2, 74.5% for pT3a, and 55.0% for pT3b tumors, respectively. Multivariate Cox model showed that PSA, Gleason score, pT category, nodal status, and surgical margins were significant independent predictors of biochemical recurrence-free survival. CONCLUSIONS: This assessment of oncologic results demonstrates that ELRP is a safe and effective procedure. On the basis of midterm follow-up data, the prognostic factors of PSA after ELRP failure are the same as those described previously in transperitoneal or open retropubic approaches. The oncologic results of ELRP also are in line with those reported with the use of the retropubic or the transperitoneal laparoscopic approaches