Androgens modulate autophagy and cell death via regulation of the endoplasmic reticulum chaperone glucose-regulated protein 78/BiP in prostate cancer cells

Pro-survival signalling mediated by the androgen receptor (AR) is implicated as a key contributor to prostate carcinogenesis. As prostate tumours are characterized by nutrient-poor, hypoxic and acidified microenvironments, one mechanism whereby AR signalling may contribute to survival is by promoting adaptation to cellular stress. Here we have identified a novel role for AR in the inhibition of autophagy induced by serum withdrawal. This blockade is attributed to AR-mediated upregulation of the endoplasmic reticulum (ER) chaperone glucose-regulated protein 78/BiP (Grp78/BiP), and occurs independently of ER stress response pathway activation. Interestingly, AR activation did not affect serum starvation-induced mammalian target of rapamycin inhibition, illustrating that the adaptive role for androgens lies not in the ability to modulate nutrient sensing, but in the promotion of ER stability. Finally, we show that the adaptive advantage conferred by AR-mediated Grp78/BiP upregulation is temporary, as upon chronic serum starvation, AR activation delayed but did not suppress the onset of autophagy and cell death. This study reveals a novel mechanism whereby maintained AR signalling promotes temporary adaptation to cellular stress and in turn may contribute to the evasion of prostate tumour cell death

Endopeptidase 24.11 activity in the human prostate cancer cell lines LNCaP and PPC-1

Human endopeptidase 24.11 (EP) occurs in greatest abundance on terminally differentiated prostate cells; thus, loss of EP could mark dedifferentiation of prostate epithelium. To identify laboratory models that would permit continuous work on the biochemistry and hormonal regulation of EP, we examined the well-differentiated LNCaP and poorly differentiated PPC-1 human prostate cancer cell lines. Ultrastructural analysis revealed that LNCaP secretes electron-dense material that resembles the particulate matter of seminal plasma, which is associated with endopeptidase activity. LNCaP medium contained EP activity while PPC-1 medium did not. Whether the apparent deletion of EP from the PPC-1 cell line is characteristic of poorly differentiated prostate adenocarcinoma is not yet clear. However, it may be relevant to the carcinogenic process that EP can limit growth of lung small carcinomas by inactivating cell growth-promoting bombesin-like peptides. Because bombesin has been identified in aggressive human prostate cancers, loss of EP in PPC-1 could represent a necessary step in transformation to aggressive phenotype. The combination of LNCaP and PPC-1, which offers well-differentiated and poorly differentiated cancer phenotypes, appears well suited to studying the relevance of EP in prostate cancer biology

Analysis of surgically-induced right bundle branch block pattern using intracardiac recording techniques.

Using intracardiac recording techniques, His bundle (H) and right ventricular apical (RVA) electrograms were recorded in 16 patients with a postoperative electrocardiographic pattern of right bundle branch block (RBBB). Their ages ranged from 5 to 12 years (mean 6.9 years) at surgery and the follow-up period was 1 to 7 years (mean 2.7 years). All were asymptomatic and in sinus rhythm at the time of study. The P-A interval was normal in all and the A-H, H-V, and V-RVA intervals were prolonged in one, one, and six patients, respectively. The V-RNA interval was normal (less than or equal to 30 msec) in ten out of the 11 patients (91%) without associated left anterior hemiblock (LAH), indicating a physiologically intact main right bundle branch, and was abnormally lengthened (45-62 msec) in all five patients (100%) with associated LAH. These findings suggest that there are two subgroups of patients with surgicall-induced RBBB pattern and the measurement of the V-RVA interval in conjunction with the H-V interval may be of ultimate importance in understanding the long-term prognostic implication of surgically-induced RBBB pattern with or without LAH