FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt

Pei, Huadong; Liang, Li; Fridley, Brooke L.; Jenkins, Gregory D.; Kalari, Krishna R.; Lingle, Wilma L.; Petersen, Gloria M.; Lou, Zhenkun; Wang, Liewei

doi:10.1016/j.ccr.2009.07.016

Cited by 635 publications

(673 citation statements)

References 28 publications

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“…Based on our results, we hypothesize that the regulation of Akt activation by CABYR-a/b is likely posttranslational, and this hypothesis is also supported by observations that gene amplification (data not shown) and total Akt protein levels do not change in CABYR-a/b-silenced cells compared with mock controls. One possible mechanism may be that CABYR-a/b indirectly regulates Akt dephosphorylation by modulating proteins that terminate Akt signaling through the dephosphorylation and inactivation of Akt, such as PHLPP (25), CTMP (26), PHLDA3 (27), and FKBP51 (28). Conversely, CABYR-a/b may also influence the activation of Akt directly or indirectly.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

Qian

Wang

et al. 2014

Molecular Cancer Research

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CABYR is a calcium-binding tyrosine phosphorylation-regulated protein that was identified as a novel cancer testis antigen in lung cancer in our previous study. However, the role of CABYR as a driver of disease progression or as a chemosensitizer is poorly understood. This study sought to investigate the relationship between the expression levels of CABYR-a/b, which are the two predominant isoforms of the five isoform proteins encoded by CABYR, and chemosensitivity in non-small cell lung cancer cells. We found that the short hairpin RNA-mediated knockdown of CABYR-a/b significantly inhibited the proliferation of NCI-H460 and A549 cells and resulted in the attenuation of Akt phosphorylation, which is constitutively active in lung cancer cells. The silencing of CABYR-a/b expression notably impacted the downstream components of the Akt pathways: decreasing the phospho-GSK-3b (Ser9) levels and increasing the expression of the p53 and p27 proteins. Furthermore, CABYR-a/b knockdown led to a significant increase in chemosensitivity in response to chemotherapeutic drugs and drug-induced apoptosis, both in vitro and in vivo. Conversely, the transient transfection of CABYR-a/b-depleted cells with constitutively active Akt partially restored the resistance to cisplatin and paclitaxel and significantly decreased the activation of GSK-3b and cleaved PARP. Taken together, our results suggest that the inhibition of CABYR-a/b is a novel method to improve the apoptotic response and chemosensitivity in lung cancer and that this cancer testis antigen is an attractive target for lung cancer drug development.

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Section: Discussionmentioning

confidence: 99%

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

Qian

Wang

et al. 2014

Molecular Cancer Research

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“…34,35 Notably, FKBP51 was found to act as a scaffolding protein to facilitate the dephosphorylation of Akt by the phosphatase PHLPP. 36,37 In cells, the interaction of FKBP51 with Akt was in part mediated by Hsp90 (FKBP51 binds to Hsp90 via its TPR domain and Akt is an established Hsp90 client). 35 However, FKBP51 could also interact with Akt directly.…”

Section: The Role Of Fkbps In Intracellular Signalingmentioning

confidence: 99%

FKBPs and the Akt/mTOR pathway

et al. 2013

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“…AKT is a key node in the signaling network, with multiple substrates that mediate processes as diverse as cell proliferation, resistance to apoptosis, and glucose and fatty acid metabolism, which are activated in a wide range of solid and hematologic malignancies (10,11). AKT activation, either directly or indirectly by loss of PTEN and other means, has been shown to mediate resistance to inhibitors of receptor tyrosine kinases such as HER2 (12,13), antihormonal agents in breast (14)(15)(16) and prostate (17)(18)(19) cancers, and chemotherapy (20)(21)(22). Therefore, it is one of the most promising targets for cancer therapy, with a considerable platform of preclinical validation.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

Davies

Greenwood

Dudley

et al. 2012

Molecular Cancer Therapeutics

389

345

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AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 mmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 mmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused doseand time-dependent reduction of PRAS40, GSK3b, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC 50 $ 0.1 mmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ( 18 F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2þ breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials. Mol Cancer Ther; 11(4); 873-87. Ó2012 AACR.

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FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt

Cited by 635 publications

References 28 publications

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

FKBPs and the Akt/mTOR pathway

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

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