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https://www.readbyqxmd.com/read/27904688/molecular-mechanism-of-prostate-cancer-cell-apoptosis-induced-by-busulfan-via-adjustment-of-androgen-receptor-phosphatization
#1
Jun Liu, Guojun Jiang, Aiping Yang, Guohui Yang, Wenjuan Yang, Yi Fang
OBJECTIVE: To probe killing effect of busulfan to prostate cancer cell without androgen and the influence of androgen receptor phosphatization and analyze its molecular mechanism. METHODS: prostate cancer cell line 22RV1, LAPC4 and LNCaP treated with busulfan under androgen-free condition underwent CCK-8 examination to probe killing ability of the medicine. Flow cytometry was used to check the influence of busulfan on apoptosis rate of prostate cancer cell line LAPC4...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27902967/the-non-receptor-tyrosine-kinase-tnk2-ack1-is-a-novel-therapeutic-target-in-triple-negative-breast-cancer
#2
Xinyan Wu, Muhammad Saddiq Zahari, Santosh Renuse, Dhanashree S Kelkar, Mustafa A Bharbuiya, Pamela L Rojas, Vered Stearns, Edward Gabrielson, Pavani Malla, Saraswati Sukumar, Nupam P Mahajan, Akhilesh Pandey
Breast cancer is the most prevalent cancer in women worldwide. About 15-20% of all breast cancers do not express estrogen receptor, progesterone receptor or HER2 receptor and hence are collectively classified as triple negative breast cancer (TNBC). These tumors are often relatively aggressive when compared to other types of breast cancer, and this issue is compounded by the lack of effective targeted therapy. In our previous phosphoproteomic profiling effort, we identified the non-receptor tyrosine kinase TNK2 as activated in a majority of aggressive TNBC cell lines...
November 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27782307/estimation-of-relative-free-energies-of-binding-using-pre-computed-ensembles-based-on-the-single-step-free-energy-perturbation-and-the-site-identification-by-ligand-competitive-saturation-approaches
#3
E Prabhu Raman, Sirish Kaushik Lakkaraju, Rajiah Aldrin Denny, Alexander D MacKerell
Accurate and rapid estimation of relative binding affinities of ligand-protein complexes is a requirement of computational methods for their effective use in rational ligand design. Of the approaches commonly used, free energy perturbation (FEP) methods are considered one of the most accurate, although they require significant computational resources. Accordingly, it is desirable to have alternative methods of similar accuracy but greater computational efficiency to facilitate ligand design. In the present study relative free energies of binding are estimated for one or two non-hydrogen atom changes in compounds targeting the proteins ACK1 and p38 MAP kinase using three methods...
October 26, 2016: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/27576506/histone-deacetylase-inhibitors-induce-proteolysis-of-activated-cdc42-associated-kinase-1-in-leukemic-cells
#4
Nisintha Mahendrarajah, Ramin Paulus, Oliver H Krämer
PURPOSE: Activated CDC42-associated kinase-1 (ACK1/TNK2) and epigenetic regulators of the histone deacetylase (HDAC) family regulate the proliferation and survival of leukemic cells. 18 HDACs fall into four classes (I-IV). We tested the impact of clinically relevant histone deacetylase inhibitors (HDACi) on ACK1 and if such drugs combine favorably with the therapeutically used ACK1 inhibitor Dasatinib. METHODS: We applied the broad-range HDACi Panobinostat/LBH589 and the class I HDAC-specific inhibitor Entinostat/MS-275 to various acute and chronic myeloid leukemia cells (AML/CML)...
November 2016: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/27387461/auto-thiophosphorylation-activity-of-src-tyrosine-kinase
#5
M Zulema Cabail, Emily I Chen, Antonius Koller, W Todd Miller
BACKGROUND: Intermolecular autophosphorylation at Tyr416 is a conserved mechanism of activation among the members of the Src family of nonreceptor tyrosine kinases. Like several other tyrosine kinases, Src can catalyze the thiophosphorylation of peptide and protein substrates using ATPγS as a thiophosphodonor, although the efficiency of the reaction is low. RESULTS: Here, we have characterized the ability of Src to auto-thiophosphorylate. Auto-thiophosphorylation of Src at Tyr416 in the activation loop proceeds efficiently in the presence of Ni(2+), resulting in kinase activation...
2016: BMC Biochemistry
https://www.readbyqxmd.com/read/26923695/novel-2-4-diaminopyrimidines-bearing-tetrahydronaphthalenyl-moiety-against-anaplastic-lymphoma-kinase-alk-synthesis-in-vitro-ex-vivo-and-in-vivo-efficacy-studies
#6
Dawn Song, Minji Lee, Chi Hoon Park, Sunjoo Ahn, Chang Soo Yun, Chong Ock Lee, Hyoung Rae Kim, Jong Yeon Hwang
A series of novel 2,4-diaminopyrimidines bearing tetrahydronaphthalenyl moiety were synthesized and evaluated for their anti-anaplastic lymphoma kinase (ALK) activities using enzymatic and cell-based assays. Among the compounds synthesized, compound 17b showed promising pharmacological results in in vitro, ex vivo, and pharmacokinetic studies. An in vivo efficacy study with compound 17b demonstrated highly potent inhibitory activity in H3122 tumor xenograft model mice. A series of kinase assays showed that compound 17b inhibited various kinases including FAK, ACK1, FGFR, RSK1, IGF-1R, among others, thus demonstrating its potential for synergistic anti-tumor activity and development as a multi-targeted non-small cell lung cancer (NSCLC) therapy...
April 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/26621748/ack1-is-a-dopamine-transporter-endocytic-brake-that-rescues-a-trafficking-dysregulated-adhd-coding-variant
#7
Sijia Wu, Karl D Bellve, Kevin E Fogarty, Haley E Melikian
The dopamine (DA) transporter (DAT) facilitates high-affinity presynaptic DA reuptake that temporally and spatially constrains DA neurotransmission. Aberrant DAT function is implicated in attention-deficit/hyperactivity disorder and autism spectrum disorder. DAT is a major psychostimulant target, and psychostimulant reward strictly requires binding to DAT. DAT function is acutely modulated by dynamic membrane trafficking at the presynaptic terminal and a PKC-sensitive negative endocytic mechanism, or "endocytic brake," controls DAT plasma membrane stability...
December 15, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26536663/ack1-overexpression-promotes-metastasis-and-indicates-poor-prognosis-of-hepatocellular-carcinoma
#8
RANDOMIZED CONTROLLED TRIAL
Xiong Lei, Yun-Feng Li, Guo-Dong Chen, Di-Peng Ou, Xiao-Xin Qiu, Chao-Hui Zuo, Lian-Yue Yang
Despite the substantial data supporting the oncogenic role of Ack1, the predictive value and biologic role of Ack1 in hepatocellular carcinoma (HCC) metastasis remains unknown. In this study, both correlations of Ack1 expression with prognosis of HCC, and the role of Ack1 in metastasis of HCC were investigated in vitro and in vivo. Our results showed that Ack1 was overexpressed in human HCC tissues and cell lines. High Ack1 expression was associated with HCC metastasis and determined as a significant and independent prognostic factor for HCC after liver resection...
December 1, 2015: Oncotarget
https://www.readbyqxmd.com/read/26025205/the-critical-role-of-akt-in-cardiovascular-function
#9
REVIEW
Prasanna Abeyrathna, Yunchao Su
Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. Beta-catenin/Tcf-4, GLI1 and Stat-3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1...
November 2015: Vascular Pharmacology
https://www.readbyqxmd.com/read/25950519/mutation-of-androgen-receptor-n-terminal-phosphorylation-site-tyr-267-leads-to-inhibition-of-nuclear-translocation-and-dna-binding
#10
Mehmet Karaca, Yuanbo Liu, Zhentao Zhang, Dinuka De Silva, Joel S Parker, H Shelton Earp, Young E Whang
Reactivation of androgen receptor (AR) may drive recurrent prostate cancer in castrate patients. Ack1 tyrosine kinase is overexpressed in prostate cancer and promotes castrate resistant xenograft tumor growth and enhances androgen target gene expression and AR recruitment to enhancers. Ack1 phosphorylates AR at Tyr-267 and possibly Tyr-363, both in the N-terminal transactivation domain. In this study, the role of these phosphorylation sites was investigated by characterizing the phosphorylation site mutants in the context of full length and truncated AR lacking the ligand-binding domain...
2015: PloS One
https://www.readbyqxmd.com/read/25945695/activated-cdc42-associated-kinase-is-up-regulated-in-non-small-cell-lung-cancer-and-necessary-for-fgfr-mediated-akt-activation
#11
Fengqing Hu, Hongcheng Liu, Xiao Xie, Ju Mei, Mingsong Wang
Activated cdc42-associated tyrosine kinase 1 (ACK1) has been reported to be implicated in non-small-cell lung cancer (NSCLC). However, the expression pattern and biological functions of ACK1 in the progression of NSCLC are not fully understood. In this study, it was found that the expression of ACK1 was significantly up-regulated in NSCLC samples compared to their adjacent normal tissues. Meanwhile, the expression of ACK1 was inversely correlated with the survival of NSCLC patients. Moreover, in the biological function studies, ACK1 was further validated to promote the growth, migration, and metastasis of NSCLC cells in vitro and in vivo...
May 2016: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/25833960/identification-of-novel-therapeutic-targets-in-acute-leukemias-with-nras-mutations-using-a-pharmacologic-approach
#12
Atsushi Nonami, Martin Sattler, Ellen Weisberg, Qingsong Liu, Jianming Zhang, Matthew P Patricelli, Amanda L Christie, Amy M Saur, Nancy E Kohl, Andrew L Kung, Hojong Yoon, Taebo Sim, Nathanael S Gray, James D Griffin
Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules (eg, RAF kinase) have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in preclinical models of acute myelogenous leukemia and acute lymphoblastic leukemia...
May 14, 2015: Blood
https://www.readbyqxmd.com/read/25699576/development-of-novel-ack1-tnk2-inhibitors-using-a-fragment-based-approach
#13
Harshani R Lawrence, Kiran Mahajan, Yunting Luo, Daniel Zhang, Nathan Tindall, Miles Huseyin, Harsukh Gevariya, Sakib Kazi, Sevil Ozcan, Nupam P Mahajan, Nicholas J Lawrence
The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process...
March 26, 2015: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/25678401/ack1-promotes-gastric-cancer-epithelial-mesenchymal-transition-and-metastasis-through-akt-pou2f1-ecd-signalling
#14
Song-Hui Xu, Jin-Zhou Huang, Man-Li Xu, Guangchuang Yu, Xing-Feng Yin, De Chen, Guang-Rong Yan
Amplification of the activated Cdc42-associated kinase 1 (ACK1) gene is frequent in gastric cancer (GC). However, little is known about the clinical roles and molecular mechanisms of ACK1 abnormalities in GC. Here, we found that the ACK1 protein level and ACK1 phosphorylation at Tyr 284 were frequently elevated in GC and associated with poor patient survival. Ectopic ACK1 expression in GC cells induced epithelial-mesenchymal transition (EMT) and promoted migration and invasion in vitro, and metastasis in vivo; the depletion of ACK1 induced the opposite effects...
June 2015: Journal of Pathology
https://www.readbyqxmd.com/read/25445114/overexpression-of-activated-cdc42-associated-kinase1-ack1-predicts-tumor-recurrence-and-poor-survival-in-human-hepatocellular-carcinoma
#15
Bin Wang, Tao Xu, Jingfeng Liu, Shengbing Zang, Lingyun Gao, Aimin Huang
Hepatocellular carcinoma (HCC) is one of the most common cancers in China. Recent research suggested that activated Cdc42-associated kinase 1 (Ack1) played an important role in facilitating tumorigenesis, tumor invasion and metastasis. However, the role of Ack1 in HCC is not clear. Herein, the expression level of Ack1 mRNA in 30 fresh HCC specimens (carcinoma, peri-carcinoma and distal-carcinoma tissues) was detected by reverse transcription-polymerase chain reaction (RT-PCR), while the expression of Ack1 protein in 18 fresh HCC specimens (carcinoma, peri-carcinoma and distal-carcinoma tissues) was analyzed by Western blotting...
December 2014: Pathology, Research and Practice
https://www.readbyqxmd.com/read/25381350/alternative-acetate-production-pathways-in-chlamydomonas-reinhardtii-during-dark-anoxia-and-the-dominant-role-of-chloroplasts-in-fermentative-acetate-production
#16
Wenqiang Yang, Claudia Catalanotti, Sarah D'Adamo, Tyler M Wittkopp, Cheryl J Ingram-Smith, Luke Mackinder, Tarryn E Miller, Adam L Heuberger, Graham Peers, Kerry S Smith, Martin C Jonikas, Arthur R Grossman, Matthew C Posewitz
Chlamydomonas reinhardtii insertion mutants disrupted for genes encoding acetate kinases (EC 2.7.2.1) (ACK1 and ACK2) and a phosphate acetyltransferase (EC 2.3.1.8) (PAT2, but not PAT1) were isolated to characterize fermentative acetate production. ACK1 and PAT2 were localized to chloroplasts, while ACK2 and PAT1 were shown to be in mitochondria. Characterization of the mutants showed that PAT2 and ACK1 activity in chloroplasts plays a dominant role (relative to ACK2 and PAT1 in mitochondria) in producing acetate under dark, anoxic conditions and, surprisingly, also suggested that Chlamydomonas has other pathways that generate acetate in the absence of ACK activity...
November 2014: Plant Cell
https://www.readbyqxmd.com/read/25257795/pdgfr-%C3%AE-activated-ack1-akt-signaling-promotes-glioma-tumorigenesis
#17
Jiannan Zhang, Tao Chen, Qin Mao, Jinbo Lin, Jun Jia, Shanquan Li, Wenhao Xiong, Yingying Lin, Zhiqiang Liu, Xiaoyu Liu, Hailiang Zhao, Guisong Wang, Duo Zheng, Shuqi Qiu, Jianwei Ge
Aberrant PDGF-PDGFR signaling and its effects on downstream effectors have been implicated in glioma development. A crucial AKT regulator, ACK1 (TNK2) has been shown to be a downstream mediator of PDGF signaling; however, the exact underlying mechanisms in gliomas remain elusive. Here, we report that in glioma cells, PDGFR-β activation enhanced the interaction between ACK1 and AKT, resulting in AKT activation. PDGF treatment consistently promoted the formation of complexes containing PDGFR-β and ACK1. Mutational analysis suggested that Y635 of ACK1 is a PDGFR-β phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT...
April 15, 2015: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/25223282/ack-kinase-regulates-ctp-synthase-filaments-during-drosophila-oogenesis
#18
Todd I Strochlic, Kevin P Stavrides, Sam V Thomas, Emmanuelle Nicolas, Alana M O'Reilly, Jeffrey R Peterson
The enzyme CTP synthase (CTPS) dynamically assembles into macromolecular filaments in bacteria, yeast, Drosophila, and mammalian cells, but the role of this morphological reorganization in regulating CTPS activity is controversial. During Drosophila oogenesis, CTPS filaments are transiently apparent in ovarian germline cells during a period of intense genomic endoreplication and stockpiling of ribosomal RNA. Here, we demonstrate that CTPS filaments are catalytically active and that their assembly is regulated by the non-receptor tyrosine kinase DAck, the Drosophila homologue of mammalian Ack1 (activated cdc42-associated kinase 1), which we find also localizes to CTPS filaments...
November 2014: EMBO Reports
https://www.readbyqxmd.com/read/25148682/ack1-tyrosine-kinase-interacts-with-histone-demethylase-kdm3a-to-regulate-the-mammary-tumor-oncogene-hoxa1
#19
Kiran Mahajan, Harshani R Lawrence, Nicholas J Lawrence, Nupam P Mahajan
Hormone therapy with the selective estrogen-receptor modulator tamoxifen provides a temporary relief for patients with estrogen receptor α (ER)-positive breast cancers. However, a subset of patients exhibiting overexpression of the HER2 receptor tyrosine kinase displays intrinsic resistance to tamoxifen therapy. Therefore, elucidating the mechanisms promoting the estrogen (E2)-independent ER-regulated gene transcription in tamoxifen-resistant breast tumors is essential to identify new therapeutic avenues to overcome drug resistance and ameliorate poor prognosis...
October 10, 2014: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/24948875/androgen-receptor-activation-in-castration-recurrent-prostate-cancer-the-role-of-src-family-and-ack1-tyrosine-kinases
#20
REVIEW
Irwin H Gelman
There is growing appreciation that castration-recurrent prostate cancer (CR-CaP) is driven by the continued expression of androgen receptor (AR). AR activation in CR-CaP through various mechanisms, including AR overexpression, expression of AR splice variants or mutants, increased expression of co-regulator proteins, and by post-translational modification, allows for the induction of AR-regulated genes in response to very low levels of tissue-expressed, so-called intracrine androgens, resulting in pathways that mediate CaP proliferation, anti-apoptosis and oncogenic aggressiveness...
2014: International Journal of Biological Sciences
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