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Dynamic impacts of the inhibition of the molecular chaperone Hsp90 on the T-cell proteome have implications for anti-cancer therapy.

Fierro-Monti I, Echeverria P, Racle J, Hernandez C, Picard D, Quadroni M - PLoS ONE (2013)

Bottom Line: Global and specific dynamic impacts, including proteostatic responses, are due to direct inhibition of Hsp90 as well as indirect effects.As a result, a decrease was detected in most proteins that changed their levels, including known Hsp90 clients.The diversity of global effects may represent a paradigm of mechanisms that are operating to shield cells from proteotoxic stress, by promoting pro-survival and anti-proliferative functions.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

ABSTRACT
The molecular chaperone Hsp90-dependent proteome represents a complex protein network of critical biological and medical relevance. Known to associate with proteins with a broad variety of functions termed clients, Hsp90 maintains key essential and oncogenic signalling pathways. Consequently, Hsp90 inhibitors are being tested as anti-cancer drugs. Using an integrated systematic approach to analyse the effects of Hsp90 inhibition in T-cells, we quantified differential changes in the Hsp90-dependent proteome, Hsp90 interactome, and a selection of the transcriptome. Kinetic behaviours in the Hsp90-dependent proteome were assessed using a novel pulse-chase strategy (Fierro-Monti et al., accompanying article), detecting effects on both protein stability and synthesis. Global and specific dynamic impacts, including proteostatic responses, are due to direct inhibition of Hsp90 as well as indirect effects. As a result, a decrease was detected in most proteins that changed their levels, including known Hsp90 clients. Most likely, consequences of the role of Hsp90 in gene expression determined a global reduction in net de novo protein synthesis. This decrease appeared to be greater in magnitude than a concomitantly observed global increase in protein decay rates. Several novel putative Hsp90 clients were validated, and interestingly, protein families with critical functions, particularly the Hsp90 family and cofactors themselves as well as protein kinases, displayed strongly increased decay rates due to Hsp90 inhibitor treatment. Remarkably, an upsurge in survival pathways, involving molecular chaperones and several oncoproteins, and decreased levels of some tumour suppressors, have implications for anti-cancer therapy with Hsp90 inhibitors. The diversity of global effects may represent a paradigm of mechanisms that are operating to shield cells from proteotoxic stress, by promoting pro-survival and anti-proliferative functions. Data are available via ProteomeXchange with identifier PXD000537.

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Related in: MedlinePlus

Both beneficial and detrimental effects of Hsp90 inhibitors on cancer-related proteins.Cancer proteins categorized by Higgins et al. [46] as oncogenes or tumour suppressors were retrieved and identified in the stSILAC data. These results were further refined and confirmed by literature mining, and organized in a protein-protein interaction network. Relative levels of proteins at 20hs after GA treatment are integrated in the graph and represented by the same colour gradient as in Fig. 2.
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pone-0080425-g004: Both beneficial and detrimental effects of Hsp90 inhibitors on cancer-related proteins.Cancer proteins categorized by Higgins et al. [46] as oncogenes or tumour suppressors were retrieved and identified in the stSILAC data. These results were further refined and confirmed by literature mining, and organized in a protein-protein interaction network. Relative levels of proteins at 20hs after GA treatment are integrated in the graph and represented by the same colour gradient as in Fig. 2.

Mentions: Protein complexes related to cancer development were identified, extracted from the Hsp90Int to be further analysed. Oncogene and tumour suppressor categories [46], including depleted and partially changed proteins gave rise to 9 different sub-graphs, which were further categorised into functional groups through literature mining (Figure 4). As expected, GA-treatment enriched several tumour suppressors and depleted critical oncoproteins and kinases (Fig. 4). However, two ‘danger zones’ were identified, where GA-treatment of T-cells appeared to be enriching oncoproteins and depleting tumour suppressors. Amongst oncogenes we found a large number of members of the Ras family of GTPases with a moderate increase, especially Rab proteins, which have been reported to be abnormally expressed in several cancers, and to be required for adhesion and migration of cancer cells [47]. The retinoblastoma protein (pRb) amid other tumour suppressors (Figure 4) appeared to be depleted. A key regulator of entry into cell division, pRb promotes G0-G1 transition when phosphorylated by CDK3/cyclin-C, and its underphosphorylated active form interacts with E2F1 and represses its transcription activity, leading to cell cycle arrest.


Dynamic impacts of the inhibition of the molecular chaperone Hsp90 on the T-cell proteome have implications for anti-cancer therapy.

Fierro-Monti I, Echeverria P, Racle J, Hernandez C, Picard D, Quadroni M - PLoS ONE (2013)

Both beneficial and detrimental effects of Hsp90 inhibitors on cancer-related proteins.Cancer proteins categorized by Higgins et al. [46] as oncogenes or tumour suppressors were retrieved and identified in the stSILAC data. These results were further refined and confirmed by literature mining, and organized in a protein-protein interaction network. Relative levels of proteins at 20hs after GA treatment are integrated in the graph and represented by the same colour gradient as in Fig. 2.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842317&req=5

pone-0080425-g004: Both beneficial and detrimental effects of Hsp90 inhibitors on cancer-related proteins.Cancer proteins categorized by Higgins et al. [46] as oncogenes or tumour suppressors were retrieved and identified in the stSILAC data. These results were further refined and confirmed by literature mining, and organized in a protein-protein interaction network. Relative levels of proteins at 20hs after GA treatment are integrated in the graph and represented by the same colour gradient as in Fig. 2.
Mentions: Protein complexes related to cancer development were identified, extracted from the Hsp90Int to be further analysed. Oncogene and tumour suppressor categories [46], including depleted and partially changed proteins gave rise to 9 different sub-graphs, which were further categorised into functional groups through literature mining (Figure 4). As expected, GA-treatment enriched several tumour suppressors and depleted critical oncoproteins and kinases (Fig. 4). However, two ‘danger zones’ were identified, where GA-treatment of T-cells appeared to be enriching oncoproteins and depleting tumour suppressors. Amongst oncogenes we found a large number of members of the Ras family of GTPases with a moderate increase, especially Rab proteins, which have been reported to be abnormally expressed in several cancers, and to be required for adhesion and migration of cancer cells [47]. The retinoblastoma protein (pRb) amid other tumour suppressors (Figure 4) appeared to be depleted. A key regulator of entry into cell division, pRb promotes G0-G1 transition when phosphorylated by CDK3/cyclin-C, and its underphosphorylated active form interacts with E2F1 and represses its transcription activity, leading to cell cycle arrest.

Bottom Line: Global and specific dynamic impacts, including proteostatic responses, are due to direct inhibition of Hsp90 as well as indirect effects.As a result, a decrease was detected in most proteins that changed their levels, including known Hsp90 clients.The diversity of global effects may represent a paradigm of mechanisms that are operating to shield cells from proteotoxic stress, by promoting pro-survival and anti-proliferative functions.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

ABSTRACT
The molecular chaperone Hsp90-dependent proteome represents a complex protein network of critical biological and medical relevance. Known to associate with proteins with a broad variety of functions termed clients, Hsp90 maintains key essential and oncogenic signalling pathways. Consequently, Hsp90 inhibitors are being tested as anti-cancer drugs. Using an integrated systematic approach to analyse the effects of Hsp90 inhibition in T-cells, we quantified differential changes in the Hsp90-dependent proteome, Hsp90 interactome, and a selection of the transcriptome. Kinetic behaviours in the Hsp90-dependent proteome were assessed using a novel pulse-chase strategy (Fierro-Monti et al., accompanying article), detecting effects on both protein stability and synthesis. Global and specific dynamic impacts, including proteostatic responses, are due to direct inhibition of Hsp90 as well as indirect effects. As a result, a decrease was detected in most proteins that changed their levels, including known Hsp90 clients. Most likely, consequences of the role of Hsp90 in gene expression determined a global reduction in net de novo protein synthesis. This decrease appeared to be greater in magnitude than a concomitantly observed global increase in protein decay rates. Several novel putative Hsp90 clients were validated, and interestingly, protein families with critical functions, particularly the Hsp90 family and cofactors themselves as well as protein kinases, displayed strongly increased decay rates due to Hsp90 inhibitor treatment. Remarkably, an upsurge in survival pathways, involving molecular chaperones and several oncoproteins, and decreased levels of some tumour suppressors, have implications for anti-cancer therapy with Hsp90 inhibitors. The diversity of global effects may represent a paradigm of mechanisms that are operating to shield cells from proteotoxic stress, by promoting pro-survival and anti-proliferative functions. Data are available via ProteomeXchange with identifier PXD000537.

Show MeSH
Related in: MedlinePlus