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High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance.

ABSTRACT: p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than did stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients.

SUBMITTER: Simpson NE

PROVIDER: S-EPMC3007122 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance.

Simpson Natalie E NE Lambert W Marcus WM Watkins Renecia R Giashuddin Shah S Huang S Joseph SJ Oxelmark Ellinor E Arju Rezina R Hochman Tsivia T Goldberg Judith D JD Schneider Robert J RJ Reiz Luiz Fernando Lima LF Soares Fernando Augusto FA Soares Fernando Augusto FA Logan Susan K SK Garabedian Michael J MJ

Cancer research 20100916 21

p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling process ...[more]

PMID: 20847343

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Project description:Allosteric interactions of the molecular chaperone Hsp90 with a large cohort of cochaperones and client proteins allow for molecular communication and event coupling in signal transduction networks. The integration of cochaperones into the Hsp90 system is driven by the regulatory mechanisms that modulate the progression of the ATPase cycle and control the recruitment of the Hsp90 clientele. In this work, we report the results of computational modeling of allosteric regulation in the Hsp90 complexes with the cochaperones p23 and Aha1. By integrating protein docking, biophysical simulations, modeling of allosteric communications, protein structure network analysis and the energy landscape theory we have investigated dynamics and stability of the Hsp90-p23 and Hsp90-Aha1 interactions in direct comparison with the extensive body of structural and functional experiments. The results have revealed that functional dynamics and allosteric interactions of Hsp90 can be selectively modulated by these cochaperones via specific targeting of the regulatory hinge regions that could restrict collective motions and stabilize specific chaperone conformations. The protein structure network parameters have quantified the effects of cochaperones on conformational stability of the Hsp90 complexes and identified dynamically stable communities of residues that can contribute to the strengthening of allosteric interactions. According to our results, p23-mediated changes in the Hsp90 interactions may provide "molecular brakes" that could slow down an efficient transmission of the inter-domain allosteric signals, consistent with the functional role of p23 in partially inhibiting the ATPase cycle. Unlike p23, Aha1-mediated acceleration of the Hsp90-ATPase cycle may be achieved via modulation of the equilibrium motions that facilitate allosteric changes favoring a closed dimerized form of Hsp90. The results of our study have shown that Aha1 and p23 can modulate the Hsp90-ATPase activity and direct the chaperone cycle by exerting the precise control over structural stability, global movements and allosteric communications in Hsp90.

Project description:BackgroundNasopharyngeal carcinoma (NPC) is a relatively common type of cancer in Southern China, with local recurrence or distant metastases even after radical treatment; consequently, it is critical to identify the patients at higher risk for these events beforehand. This study aimed to assess the prognostic value of regional lymph node density (RLND) associated nomograms in NPC and to evaluate the utility of nomograms in risk stratification.MethodsA total of 610 NPC patients without distant metastases (425 in the training and 185 in the validation cohort) were enrolled. The MRI-identified nodal features and clinical characteristics were documented, and the RLND was calculated. Cox analyses were conducted to identify prognostic-associated factors. Nomograms were generated based on the multivariate analysis results. The predictive accuracy and discriminative ability of the nomogram models were determined using the concordance index (C-index), receiver operating characteristic (ROC) curve, and calibration curve; the results were compared with those of the tumor-node-metastasis (TNM) classification. Decision curve analysis (DCA) and C-index were used to assess the prognostic effect and added discriminative ability of RLND. We also estimated the optimal RLND-based nomogram score cut-off values for survival prediction.ResultsRLND was an independent predictor of overall survival (OS) and disease-free survival (DFS), with hazard ratios of 1.36 and 1.30, respectively. RLND was utilized in the construction of nomograms, alongside other independent prognostic factors. The RLND-based nomogram models presented a more effective discriminative ability than the TNM classification for predicting OS (C-index, 0.711 vs. 0.680) and DFS (C-index, 0.681 vs. 0.669), with favorable calibration and consistency. The comparison of C-index values between the nomogram models with and without RLND provided substantiation of the crucial role RLND plays in these models. DCA confirmed the satisfactory clinical practicability of RLND. Moreover, the nomograms were used to categorize the patients into three groups (high-, middle-, and low-risk), and the Kaplan-Meier curves showed significant differences in prognosis between them (p < 0.05). These results were verified in the validation cohort.ConclusionRLND stands as a robust prognostic factor in NPC. The RLND-based nomograms excel in predicting survival, surpassing the TNM classification.

Dataset Information

High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance.

Publications

High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance.

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