Prostate cancer is the most prevalent cancer in males, and treatment options are limited for advanced forms of the disease. Loss of the PTEN and TP53 tumor suppressor genes is commonly observed in prostate cancer, whereas their compound loss is often observed in advanced prostate cancer. Here, we show that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the prosurvival PI3K-AKT signaling pathway limits the efficacy of a PARP single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human prostate cancer cell lines and in a Pten/Trp53-deficient mouse model of advanced prostate cancer. Our findings, therefore, identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient prostate cancer.The paucity of therapeutic options in advanced prostate cancer displays an urgent need for the preclinical assessment of novel therapeutic strategies. We identified differential therapeutic vulnerabilities that emerge upon the loss of both PTEN and p53, and observed that combined inhibition of PARP and PI3K provides increased efficacy in hormone-insensitive advanced prostate cancer.
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that function via transcript degradation or translational inhibition, depending on the degree of complementarity with their target transcripts. They often exhibit temporal, spatial and developmental-stage specific expression, and have been found to be frequently dysregulated in multiple human diseases including various cancers. Numerous experimental and bioinformatic approaches have identified miRNAs that control cancer initiation and progression by directly targeting key oncogenes or tumor suppressors. PTEN (phosphatase and tensin homolog deleted on chromosome 10) is one of the most frequently disrupted tumor suppressor genes in multiple human cancers. PTEN is particularly susceptible to miRNA regulation as subtle changes in its dose have been shown to have a profound effect on tumorigenesis in vivo. Here we will review emerging evidence describing a vast layer of miRNA-mediated PTEN regulation, with a specific focus on their function in animal models in vivo, therapeutic implications, and directions for future research.
<div>Abstract<p>Aurora B is critically involved in ensuring proper cytokinesis and maintaining genomic stability. The tumor suppressor RASSF1A regulates cell cycle progression by regulating mitotic progression, G<sub>1</sub>-S transition, and microtubule stability. We previously reported that both Aurora A and Aurora B phosphorylate RASSF1A, and showed that phosphorylation of RASSF1A by Aurora A blocks the inhibitory function of RASSF1A toward anaphase-promoting complex-Cdc20. However, the role of Aurora B–mediated RASSF1A phosphorylation remains unknown. Here, we show that phosphorylation of RASSF1A on Ser203 by Aurora B during late mitosis has a critical role in regulating cytokinesis. Notably, RASSF1A interacts with Syntaxin16, a member of the t-SNARE family, at the midzone and midbody during late mitosis. Aurora B is required for this interaction and for the subsequent recruitment of Syntaxin16 to the midzone and midbody, a prerequisite for the successful completion of cytokinesis. Furthermore, Aurora B depletion results in a failure of Syntaxin16 to properly localize to the midzone and midbody, a mislocalization that was prevented by overexpression of the phosphomimetic RASSF1A (S203D) mutant. Finally, either depletion of Syntaxin16 or expression of the nonphosphorylatable RASSF1A (S203A) mutant results in cytokinesis defects. Our findings implicate Aurora B–mediated phosphorylation of RASSF1A in the regulation of cytokinesis. [Cancer Res 2009;69(22):8540–4]</p></div>
Dianthus japonicus Thunb. (D. japonicus) is a biennial with promising floricultural traits, but its commercial appeal is limited by the long time between propagation and flowering. We assessed the effect of juvenile phase, vernalization, and photoperiod on flowering of D. japonicus. Plants were grown in a plug until they had acquired nine, 14, or 16 leaf pairs, and then exposed to a vernalization period of 0, 3, 6, or 12 weeks at 5°C. At the end of the vernalization period, plants were transferred to either long-day treatment or short-day treatment for 10 weeks. In D. japonicus, the numbers of new nodes and leaves were correlated with the vernalization period. Plant height was correlated with the number of leaf pairs. As the vernalization period lengthened, the plants produced more nodes and leaves regardless of their growth stage. The maximum plant height increase was over 24.7 cm in the plants that had 16 leaf pairs at 10 weeks after the start of the photoperiod treatment, regardless of the photoperiod. Plants with 14 or 16 leaf pairs and a vernalization period of 12 weeks flowered regardless of photoperiod treatment. None of the plants that had been vernalized for less than 12 weeks flowered or produced flower buds. We noted a significant difference in the flowering response among plants based on the number of leaf pairs and vernalization period. We conclude that D. japonicus plants must form 14 to 16 leaf pairs before they can respond to vernalization and require at least 12 weeks of vernalization before flowering. This species has a qualitative response to vernalization and is day-neutral.
Ubiquitin-conjugating enzyme E2O (UBE2O) is expressed preferentially in metabolic tissues, but its role in regulating energy homeostasis has yet to be defined. Here we find that UBE2O is markedly upregulated in obese subjects with type 2 diabetes and show that whole-body disruption of Ube2o in mouse models in vivo results in improved metabolic profiles and resistance to high-fat diet-induced (HFD-induced) obesity and metabolic syndrome. With no difference in nutrient intake, Ube2o-/- mice were leaner and expended more energy than WT mice. In addition, hyperinsulinemic-euglycemic clamp studies revealed that Ube2o-/- mice were profoundly insulin sensitive. Through phenotype analysis of HFD mice with muscle-, fat-, or liver-specific knockout of Ube2o, we further identified UBE2O as an essential regulator of glucose and lipid metabolism programs in skeletal muscle, but not in adipose or liver tissue. Mechanistically, UBE2O acted as a ubiquitin ligase and targeted AMPKα2 for ubiquitin-dependent degradation in skeletal muscle; further, muscle-specific heterozygous knockout of Prkaa2 ablated UBE2O-controlled metabolic processes. These results identify the UBE2O/AMPKα2 axis as both a potent regulator of metabolic homeostasis in skeletal muscle and a therapeutic target in the treatment of diabetes and metabolic disorders.
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