Abstract 4379: Activating the prostaglandin I2-IP signaling suppresses metastasis in lung cancer

Minami, Yoshinori; Endo, Satoshi; Okumura, Shunsuke; Shibukawa, Kiyoko; Sasaki, Takaaki; Ohsaki, Yoshinobu

doi:10.1158/1538-7445.am2012-4379

Cited by 2 publications

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“…In wild-type TP53 and mutant PTEN U87MG cells, TLK1 knockdown significantly downregulated and deactivated p70s6k (Thr389). The 70-kDa ribosomal P70S6 kinase is a downstream target of the PI3K/mTOR pathway that regulates cell growth and G1 cell cycle progression by inducing the cellular translational machinery (54). P70s6k is commonly upregulated in breast cancer and GBM (55,56).…”

Section: Regulation Of Downstream Tlk1 Survival Pathwaysmentioning

confidence: 99%

Knockdown of Tousled‑like kinase 1 inhibits survival of glioblastoma multiforme cells

et al. 2020

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Glioblastoma multiforme (GBM) is an aggressive type of brain tumour that commonly exhibits resistance to treatment. The tumour is highly heterogenous and complex kinomic alterations have been reported leading to dysregulation of signalling pathways. The present study aimed to investigate the novel kinome pathways and to identify potential therapeutic targets in GBM. Meta-analysis using Oncomine identified 113 upregulated kinases in GBM. RNAi screening was performed on identified kinases using ON-TARGETplus siRNA library on LN18 and U87MG. Tousled-like kinase 1 (TLK1), which is a serine/threonine kinase was identified as a potential hit. In vitro functional validation was performed as the role of TLK1 in GBM is unknown. TLK1 knockdown in GBM cells significantly decreased cell viability, clonogenicity, proliferation and induced apoptosis. TLK1 knockdown also chemosensitised the GBM cells to the sublethal dose of temozolomide. The downstream pathways of TLK1 were examined using microarray analysis, which identified the involvement of dNA replication, cell cycle and focal adhesion signalling pathways. In vivo validation of the subcutaneous xenografts of stably transfected sh-TLK1 U87MG cells demonstrated significantly decreased tumour growth in female BALB/c nude mice. Together, these results suggested that TLK1 may serve a role in GBM survival and may serve as a potential target for glioma.

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Section: Regulation Of Downstream Tlk1 Survival Pathwaysmentioning

confidence: 99%

Knockdown of Tousled‑like kinase 1 inhibits survival of glioblastoma multiforme cells

et al. 2020

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“…Beraprost, an analogue to prostacyclin or PGI2, is commonly used for arterial pulmonary hypertension and has multiple physiological effects such as endothelial vasodilation, inhibition of platelet aggregation, leukocyte adhesion, and vascular smooth muscle cell proliferation (Wang et al 2011). Activation of the PGI2 signalling pathway by beraprost sodium suppressed lung cancer metastases by preventing maturation of angiogenesis (Yoshinori Minami et al 2012). It was also reported to enhance permeability and retention (EPR) of solid tumors by decreasing tumor blood flow by 70%, hence inhibiting tumor growth.…”

Section: Discussionmentioning

confidence: 99%

In silico homology modelling and identification of Tousled-like kinase 1 inhibitors for glioblastoma therapy via high throughput virtual screening protein-ligand docking

Ibrahim

Danjuma

et al. 2016

Preprint

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Background: Glioblastoma multiforme (GBM) is a grade IV brain tumor that arises from star-shaped glial cells supporting neural cells called astrocytes. The survival of GBM patients remains poor despite many specific molecular targets that have been developed and used for therapy. Tousled-like kinase 1 (TLK1), a serine-threonine kinase, was identified to be overexpressed in cancers such as GBM. TLK1 plays an important role in controlling chromosomal aggregation, cell survival and proliferation. In vitro studies suggested that TLK1 is a potential target for some cancers; hence, the identification of suitable molecular inhibitors for TLK1 is warranted as a new therapeutic agents in GBM. To date, there is no structure available for TLK1. In this study, we aimed to create a homology model of TLK1 and to identify suitable molecular inhibitors or compounds that are likely to bind and inhibit TLK1 activity via in silico high-throughput virtual screening (HTVS) protein-ligand docking. Methods: 3D homology models of TLK1 were derived from various servers including HOmology ModellER, i-Tasser, Psipred and Swiss Model. All models were evaluated using Swiss Model Q-Mean server. Only one model was selected for further analysis. Further validation was performed using PDBsum, 3d2go, ProSA, Procheck analysis and ERRAT. Energy minimization was performed using YASARA energy minimization server. Subsequently, HTVS was performed using Molegro Virtual Docker 6.0 and candidate ligands from ligand.info database. Ligand-docking procedures were analyzed at the putative catalytic site of TLK1. Drug-like molecules were filtered using FAF-Drugs3, which is an ADME-Tox filtering program. Results and conclusion: High quality homology models were obtained from the Aurora B kinase (PDB ID:4B8M) derived from Xenopus levias structure that share 33% sequence identity to TLK1. From the HTVS ligand-docking, two compounds were identified to be the potential inhibitors as it did not violate the Lipinski rule of five and the CNS-based filter as a potential drug-like molecule for GBM.

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Abstract 4379: Activating the prostaglandin I2-IP signaling suppresses metastasis in lung cancer

Cited by 2 publications

References 0 publications

Knockdown of Tousled‑like kinase 1 inhibits survival of glioblastoma multiforme cells

Knockdown of Tousled‑like kinase 1 inhibits survival of glioblastoma multiforme cells

In silico homology modelling and identification of Tousled-like kinase 1 inhibitors for glioblastoma therapy via high throughput virtual screening protein-ligand docking

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