TitleAffinity-based proteomics reveal cancer-specific networks coordinated by Hsp90.
Publication TypeJournal Article
Year of Publication2011
AuthorsMoulick, Kamalika, Ahn James H., Zong Hongliang, Rodina Anna, Cerchietti Leandro, DaGama Erica M. Gomes, Caldas-Lopes Eloisi, Beebe Kristin, Perna Fabiana, Hatzi Katerina, Vu Ly P., Zhao Xinyang, Zatorska Danuta, Taldone Tony, Smith-Jones Peter, Alpaugh Mary, Gross Steven S., Pillarsetty Nagavarakishore, Ku Thomas, Lewis Jason S., Larson Steven M., Levine Ross, Erdjument-Bromage Hediye, Guzman Monica L., Nimer Stephen D., Melnick Ari, Neckers Len, and Chiosis Gabriela
JournalNat Chem Biol
Date Published2011 Sep 25
KeywordsAnimals, Antineoplastic Agents, Benzodioxoles, Cell Line, Tumor, Computational Biology, Drug Discovery, Gene Expression Regulation, Neoplastic, HSP90 Heat-Shock Proteins, Humans, Neoplasms, Proteomics, Purines, Signal Transduction

<p>Most cancers are characterized by multiple molecular alterations, but identification of the key proteins involved in these signaling pathways is currently beyond reach. We show that the inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes and affinity captures Hsp90-dependent oncogenic client proteins. We have used PU-H71 affinity capture to design a proteomic approach that, when combined with bioinformatic pathway analysis, identifies dysregulated signaling networks and key oncoproteins in chronic myeloid leukemia. The identified interactome overlaps with the well-characterized altered proteome in this cancer, indicating that this method can provide global insights into the biology of individual tumors, including primary patient specimens. In addition, we show that this approach can be used to identify previously uncharacterized oncoproteins and mechanisms, potentially leading to new targeted therapies. We further show that the abundance of the PU-H71-enriched Hsp90 species, which is not dictated by Hsp90 expression alone, is predictive of the cell's sensitivity to Hsp90 inhibition.</p>

Alternate JournalNat Chem Biol
PubMed ID21946277
PubMed Central IDPMC3265389
Grant List1 DP2 OD007399-01 / OD / NIH HHS / United States
U01 AG032969-03 / AG / NIA NIH HHS / United States
R01 CA155226 / CA / NCI NIH HHS / United States
P30 CA08748 / CA / NCI NIH HHS / United States
R21 CA158609 / CA / NCI NIH HHS / United States
P50-CA86483 / CA / NCI NIH HHS / United States
R01 CA155226-02 / CA / NCI NIH HHS / United States
U01 AG032969 / AG / NIA NIH HHS / United States
R01 CA172546 / CA / NCI NIH HHS / United States
R01 CA155226-01A1 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
DP2 OD007399 / OD / NIH HHS / United States
1U01 AG032969-01A1 / AG / NIA NIH HHS / United States
1R01 CA155226-01 / CA / NCI NIH HHS / United States