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Updated: Jul 13, 2026
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Proteome-wide changes induced by the Hsp90 inhibitor, geldanamycin in anaplastic large cell lymphoma cells
Jonathan A Schumacher1, David K Crockett, Kojo S J Elenitoba-Johnson
1Associated and Regional University Pathologists (ARUP), Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
Abstract:
The molecular chaperone heat shock protein 90 (Hsp90) affects the function of many oncogenic signaling proteins including nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressed in anaplastic large cell lymphoma (ALCL). While ALK-positive ALCL cells are sensitive to the Hsp90 inhibitor and the geldanamycin (GA) analog, 17-allylamino-17-demethoxygeldanamycin (17-AAG), the proteomic effects of these drugs on ALK-positive ALCL cells are unpublished. In this study, we investigated the cellular, biologic, and proteomic changes occurring in ALK-positive ALCL cells in response to GA treatment. GA induced G2/M cell cycle arrest and caspase-3-mediated apoptosis. Furthermore, quantitative proteomic changes analyzed by cleavable isotope-coded affinity tag-LC-MS/MS (cICAT-LC-MS/MS) identified 176 differentially expressed proteins. Out of these, 49 were upregulated 1.5-fold or greater and 70 were downregulated 1.5-fold or greater in GA-treated cells. Analysis of biological functions of differentially expressed proteins revealed diverse changes, including induction of proteins involved in the 26S proteasome as well as downregulation of proteins involved in signal transduction and protein and nucleic acid metabolism. Pathway analysis revealed changes in MAPK, WNT, NF-kappaB, TGFbeta, PPAR, and integrin signaling components. Our studies reveal some of the molecular and proteomic consequences of Hsp90 inhibition in ALK-positive ALCL cells and provide novel insights into the mechanisms of its diverse cellular effects.
Insights
Heat shock protein 90 (Hsp90) inhibition in ALK-positive anaplastic large cell lymphoma (ALCL) cells with geldanamycin (GA) causes cell cycle arrest and apoptosis. Proteomic analysis revealed significant changes in protein expression, impacting various cellular pathways.
Area of Science:
- Oncology
- Molecular Biology
- Proteomics
Background:
- Heat shock protein 90 (Hsp90) is crucial for oncogenic signaling proteins, including NPM-ALK in ALK-positive anaplastic large cell lymphoma (ALCL).
- Hsp90 inhibitors like 17-AAG show sensitivity in ALK-positive ALCL cells, but their proteomic effects remain largely uncharacterized.
Purpose of the Study:
- To investigate the cellular, biological, and proteomic alterations in ALK-positive ALCL cells following treatment with the Hsp90 inhibitor geldanamycin (GA).
Main Methods:
- Quantitative proteomic analysis using cleavable isotope-coded affinity tag-LC-MS/MS (cICAT-LC-MS/MS) was employed.
- Cellular effects including cell cycle progression and apoptosis were assessed.
- Bioinformatic analysis was used to identify differentially expressed proteins and affected pathways.
Main Results:
- Geldanamycin (GA) treatment induced G2/M cell cycle arrest and caspase-3-mediated apoptosis in ALK-positive ALCL cells.
- Proteomic analysis identified 176 differentially expressed proteins, with 49 upregulated and 70 downregulated (≥1.5-fold).
- Affected biological functions included the 26S proteasome, signal transduction, and nucleic acid metabolism, with pathway analysis revealing alterations in MAPK, WNT, NF-kappaB, TGFbeta, PPAR, and integrin signaling.
Conclusions:
- Hsp90 inhibition by GA triggers significant proteomic and cellular changes in ALK-positive ALCL cells.
- These findings offer novel insights into the molecular mechanisms underlying the diverse cellular effects of Hsp90 inhibition in this lymphoma subtype.
