Androgen receptor (AR) is essential for the maintenance of the male reproductive systems and is critical for the carcinogenesis of human prostate cancers (PCas). D-type cyclins are closely related to the repression of AR function. It has been well documented that cyclin D1 inhibits AR function through multiple mechanisms, but the mechanism of how cyclin D3 exerts its repressive role in the AR signaling pathway remains to be identified. In the present investigation, we demonstrate that cyclin D3 and the 58-kDa isoform of cyclin-dependent kinase 11 (CDK11 p58 ) repressed AR transcriptional activity as measured by reporter assays of transformed cells and prostate-specific antigen expression in PCa cells. AR, cyclin D3, and CDK11 p58 formed a ternary complex in cells and were colocalized in the luminal epithelial layer of the prostate. AR activity is controlled by phosphorylation at specific sites. We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11 p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1). Furthermore, androgen-dependent proliferation of PCa cells was inhibited by cyclin D3/CDK11 p58 through AR repression. These data suggest that cyclin D3/CDK11 p58 signaling is involved in the negative regulation of AR function.Androgen receptor (AR), a member of the nuclear receptor family, directly regulates patterns of gene expression in response to the steroids testosterone and dihydrotestosterone (DHT) and is subsequently involved in the regulation of the development and differentiation of the male reproductive system (10). Similar to other steroid receptors, AR contains a transactivation domain (TAD), also named AF-1, in its N terminus, a ligand binding domain (LBD) in its C terminus, a DNA-binding domain (DBD), and a hinge region between the TAD and LBD. The transcriptional activation unit 1 (TAU1) and TAU5 motifs in the AR N-terminal domain (NTD) (residues 101 to 370 and 360 to 485, respectively) as well as the AF-2 motif in the AR LBD have been implicated in directly contacting p160 proteins and mediating transcription (1,23,31,48).AR is a phosphoprotein whose function is regulated by the modulation of its phosphorylation status at different sites (4). The consensus phosphorylation sites found in AR indicate that AR could be a substrate for DNA-dependent kinase, protein kinase A, protein kinase C, mitogen-activated protein kinase, and casein kinase 2 (4). Ser-16, Ser-81, Ser-94, Ser-256, Ser-308, Ser-424, and Ser-650 have been identified as being phosphorylation sites of AR by mutagenesis, peptide mapping, and mass spectrometry (6, 60). Recently, several Ser/Thr protein kinases have been found to phosphorylate AR at the abovementioned sites in vitro and in vivo. For example, AR Ser-515 is phosphorylated by mitogen-activated protein kinase, Ser-213 and Ser-791 are phosphorylated by Akt, and Ser-650 is phosphorylated by p38␣ and JNK1 (17,30,57).More and more studies suggest that cyclins and cyclin-dependent kinases (CDKs) are also involved in th...

Diphyllin is a natural component of traditional Chinese medicine, which effectively inhibits V-ATPase activity and affects the progression of cancer. However, few studies have been conducted on esophageal cancer, and the mechanisms remain to be elucidated. The present study revealedthat diphyllin inhibited proliferation and induced S arrest in esophageal cancer cell lines TE-1 and ECA-109. Further experiments revealed that diphyllin inhibited V-ATPase activity and decreased the mRNA expression of mammalian target of rapamycin complex 1 (mTORC1), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF). The present study also revealed that diphyllin inhibited proliferation and reduced the formation of new blood vessels. Diphyllin inhibited blood metastasis by regulating the mTORC1/HIF-1α-/VEGF pathway, therefore it could be considered as a new V-ATPase inhibitor to treat esophageal cancer.