Identification of proteomic changes induced in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma in response to the heat shock protein 90 inhibitor geldanamycin

Anaplastic large cell lymphoma (ALCL) is a subset of non-Hodgkin lymphoma that commonly express the t(2;5)(p23;q35) chromosomal translocation, resulting in overexpression of the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncoprotein. ALK harbors a cytoplasmic tyrosine kinase domain that has been shown to associate with and phosphorylate a number of adaptor proteins that initiate transcription signaling and inhibit apoptosis. Heat shock protein 90 (Hsp90) is a molecular chaperone involved in folding of a variety of substrate proteins including p53, Akt/PKB, and NPM-ALK. Geldanamycin (GA) is a benzoquinone ansamycin that binds to and inhibits heat shock protein 90 (Hsp90) from performing its chaperone duties, resulting in ubiquitin-mediated proteasomal degradation of unfolded client proteins. Here we describe a study directed at identifying the molecular mechanisms and establishing some of the proteomic changes induced in NPM-ALK-overexpressing cells due to GA inhibition of Hsp90 function. Our results demonstrate that GA induces G2/M cell cycle arrest and caspase-3 mediated apoptosis. Furthermore, proteomic analysis identified a total of 176 differentially expressed proteins including novel proteins previously unassociated with NPM-ALK survival. Our studies demonstrate some of the molecular mechanisms and novel proteomic changes in NPM-ALK-overexpressing cells induced by GA inhibition of Hsp90.