Integrin-linked kinase (ILK) represents a relevant target for cancer therapy in light of its role in promoting oncogenesis and tumor progression. Through the screening of an in-house focused compound library, we identified N-Methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide (22) as a novel ILK inhibitor (IC50, 0.6 μM), which exhibited high in vitro potency against a panel of prostate and breast cancer cell lines (IC50, 1 – 2.5 μM), while normal epithelial cells were unaffected. Compound 22 facilitated the dephosphorylation of Akt at Ser-473 and other ILK targets, including glycogen synthase kinase-3β and myosin light chain. Moreover, 22 suppressed the expression of the transcription/translation factor YB-1 and its targets HER2 and EGFR in PC-3 cells, which could be rescued by the stable expression of constitutively active ILK. Evidence indicates that 22 induced autophagy and apoptosis, both of which were integral to its antiproliferative activity. Together, this broad spectrum of mechanisms underlies the therapeutic potential of 22 in cancer treatment, which is manifested by its in vivo efficacy as a single oral agent in suppressing PC-3 xenograft tumor growth.

This study identifies a novel mechanism by which thiazolidinediones mediate cyclin D1 repression in prostate cancer cells. Based on the finding that the thiazolidinedione family of peroxisome proliferator-activated receptor ␥ (PPAR␥) agonists mediated PPAR␥-independent cyclin D1 degradation, we developed a novel PPAR␥-inactive troglitazone derivative, STG28, with high potency in cyclin D1 ablation. STG28-mediated cyclin D1 degradation was preceded by Thr-286 phosphorylation and nuclear export, which however, were independent of glycogen synthase kinase 3␤. Mutational analysis further confirmed the pivotal role of Thr-286 phosphorylation in STG28-induced nuclear export and proteolysis. Of several kinases examined, inhibition of IB kinase ␣ blocked STG28-mediated cytoplasmic sequestration and degradation of cyclin D1. Pulldown of ectopically expressed Cul1, the scaffold protein of the Skp-Cullin-F-box E3 ligase, in STG28-treated cells revealed an increased association of cyclin D1 with ␤-TrCP, whereas no specific binding was noted with other F-box proteins examined, including Skp2, Fbw7, Fbx4, and Fbxw8. This finding represents the first evidence that cyclin D1 is targeted by ␤-TrCP. Moreover, ␤-TrCP expression was up-regulated in response to STG28, and ectopic expression and small interfering RNA-mediated knockdown of ␤-TrCP enhanced and protected against STG28-facilitated cyclin D1 degradation, respectively. Because cyclin D1 lacks the DSG destruction motif, mutational and modeling analyses indicate that cyclin D1 was targeted by ␤-TrCP through an unconventional recognition site, 279 EEVDLACpT 286 , reminiscent to that of Wee1. Moreover, we obtained evidence that this ␤-TrCP-dependent degradation takes part in controlling cyclin D1 turnover when cancer cells undergo glucose starvation, which endows physiological relevance to this novel mechanism.Substantial evidence indicates that overexpression of the cell cycle control gene CCND1 represents a key mechanism underlying tumorigenesis, tumor progression, and metastasis in a variety of human cancers (1-6). Cyclin D1 serves as the regulatory subunit of cyclin-dependent kinases (CDKs) 4 and 6 and exhibits the ability to bind and sequester the CDK inhibitor p27 (5, 6). Together, these functions facilitate cyclin-dependent kinase-mediated phosphorylating inactivation of the retinoblastoma protein (pRb), resulting in G 1 /S progression. Moreover, cyclin D1 may regulate gene transcription through physical associations with a plethora of transcriptional factors, coactivators, and corepressors that govern histone acetylation and chromatin remodeling proteins (5). The concerted action of these cyclin-dependent kinase-dependent and -independent functions underscores the oncogenic potential of cyclin D1 in many forms of cancer (7). Transcriptional suppression of cyclin D1 expression has been shown to block tumorigenesis or to reverse the transformed phenotype of human esophageal (8), lung (9), colon (10), pancreatic (11), gastric (12), melanoma (13), and squamous cancer cell...

Abstract-To enhance the cost effectiveness of the distribution automation system (DAS), this paper proposes the immune algorithm (IA) to derive the optimal placement of switching devices by minimizing the total cost of customer service outage and investment cost of line switches. The reliability index of each service zone defined by the boundary switches is derived to solve the expected energy not served due to fault contingency, and the customer interruption cost is then determined according to the customer type and power consumption within the service zone. To demonstrate the effectiveness of proposed IA methodology to solve the optimal placement of line switches, a practical distribution system of Taiwan Power Company (Taipower) is selected for computer simulation to explore the cost benefit of line switch placement for DAS.Index Terms-Distribution automation system (DAS), immune algorithm (IA), outage management system (OMS).

Vitamin E is a fat-soluble vitamin that includes isomers of tocopherols and tocotrienols which are known for their antioxidant properties. Tocopherols are the predominant form encountered in the diet and through supplementation, and have garnered interest for their potential cancer therapeutic and chemopreventive effects, which include the dephosphorylation of Akt, a serine/threonine kinase that plays a pivotal role in important cellular processes, such as cell growth, survival, metabolism and motility. Full catalytic activation of Akt requires phosphorylation at both Thr308 and Ser473. Dephosphorylation of Ser473 drastically reduces Akt catalytic activity and the number of downstream substrates it can regulate. The mechanism by which α- and γ-tocopherol facilitate the selective dephosphorylation of the kinase Akt at Ser473 was investigated. We showed that this site-specific Akt dephosphorylation was mediated through the pleckstrin homology (PH) domain-dependent recruitment to the plasma membrane of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase, isoform 1), a phosphatase that dephosphorylates Akt at Ser473. The ability of α- and γ-tocopherol to induce PHLPP-mediated Akt inhibition established PHLPP as a “druggable” target. We structurally optimized these tocopherols to obtain derivatives with greater in vitro potency and in vivo tumor-suppressive activity in two prostate xenograft tumor models. Binding affinities for the PH domains of Akt and PHLPP1 were greater than for other PH domain-containing proteins, which may underlie the preferential membrane recruitment of these proteins. Molecular modeling revealed the structural determinants of the interaction with the PH domain of Akt that may inform strategies for continued structural optimization. These findings describe a mechanism by which tocopherols facilitate the dephosphorylation of Akt at Ser473, thereby providing insights into the mode of antitumor action of tocopherols and a rationale for the translational development of tocopherols into novel PH domain-targeted Akt inhibitors.

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