Dataset Information

Global proteome changes of normal NIH 3T3 versus Ras-transformed NIH cells treated with 3 different Hsp90 inhibitors (geldanamycin, PU-H71 and pochoxime A)

ABSTRACT: Heat shock protein 90 (Hsp90) is a major hub in the protein network that maintains cellular homeostasis and function. The qualitative and quantitative changes and rewiring of this protein network in tumor cells make them vastly dependent on Hsp90, and as a consequence its inhibition creates a profound transformation in the proteome. Here, we analyze our most recent effort that take advantage of the druggability of Hsp90 in order to understand the global changes at the proteome level that this inhibition produces. The considerable impact that the targeting of Hsp90 has on the structure of these protein networks shows that the interactome becomes laxer and presumably less efficient in communicating changes and stimuli to maintain cellular homeostasis. The lack of a systematic and proteome-wide study with genetically really comparable and matched normal and cancer cells that address the differential sensitivities to Hsp90 inhibitors, motivated us to conduct one. The transformation of NIH-3T3 cells from normal to tumoral with an oncogenic Ras mutant (Ras-T) establishes a new program of protein abundance that is efficiently targeted by Hsp90 inhibitors. Surprisingly, three different inhibitors (Geldanamycin"GA", PU-H71"PU" and Pochoxime"PX") affect a characteristic set of actors of this program. Studies like the one presented here, showing how the human proteome is changed and shaped by targeting Hsp90 could set the stage for the pharmacoproteomic profiling of responses to sets of different inhibitors and of cancer types with different molecular backgrounds. These drug-profiling analyses will be essential for the development of tailored Hsp90 inhibitors for the treatment of different tumor types and for the use in personalized medicine.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Didier PIcard

PROVIDER: PXD009055 | JPOST Repository | Mon Feb 11 00:00:00 GMT 2019

REPOSITORIES: jPOST

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Publications

The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity.

Echeverria Pablo C PC Bhattacharya Kaushik K Joshi Abhinav A Wang Tai T Picard Didier D

PloS one 20190206 2

The molecular chaperone Hsp90 is an essential and highly abundant central node in the interactome of eukaryotic cells. Many of its large number of client proteins are relevant to cancer. A hallmark of Hsp90-dependent proteins is that their accumulation is compromised by Hsp90 inhibitors. Combined with the anecdotal observation that cancer cells may be more sensitive to Hsp90 inhibitors, this has led to clinical trials aiming to develop Hsp90 inhibitors as anti-cancer agents. However, the sensiti ...[more]

PMID: 30726209

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Project description:About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results. A375p cells treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours. mRNA from A375p cells was extrated using RNeasy mini kit (Qiagen, Germany) according to the manufacturer's instructions. Cells were previously treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours.

Dataset Information

Global proteome changes of normal NIH 3T3 versus Ras-transformed NIH cells treated with 3 different Hsp90 inhibitors (geldanamycin, PU-H71 and pochoxime A)

Publications

The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity.

Similar Datasets

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