Support is requested in this competitive renewal to continue our studies of mechanisms of acquired drug resistance. We propose a comprehensive study of the kinds of changes in protein abundance and structures that occur in cancer cells when they become resistant to different chemotherapeutic agents. Mass spectrometry-based proteomics strategies will be used to compare the abundances and structures of proteins in MCF-7 human breast cancer cells with three sublines selected by exposure to etoposide, mitoxantrone and melphalan. It is expected that a much larger array of proteins will be found to be altered than has been previously recognized. We also expect that thoughtful consideration of the kinds of changes observed will provide new insights into mechanisms of acquired resistance, and into the hyper-sensitivity of transformed cells. New therapeutic targets may be identified. This is not envisioned as a high throughput project, but rather, overlapping and reiterative comparisons of organelles and sub-fractions will be made to allow structural changes due to mutations or post-translational modifications to be recognized and elucidated. In a parallel and related investigation, patterns of protein alkylation by radio-isotope labeled melphalan will be compared in susceptible and resistant cells, sub- fractions and organelles. Correlations, or the lack thereof, will be sought between the nature of the alkytation targets, changes in the alkylation targets, and changes in cell biochemistry defined in the comparative study.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM021248-30
Application #
6685318
Study Section
Special Emphasis Panel (ZRG1-BECM (01))
Program Officer
Edmonds, Charles G
Project Start
1987-07-01
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
30
Fiscal Year
2004
Total Cost
$359,985
Indirect Cost
Name
University of Maryland College Park
Department
Chemistry
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Rose, Rebecca L; Choksawangkarn, Waeowalee; Fenselau, Catherine (2018) Application of Higher Density Iron Oxide Nanoparticle Pellicles to Enrich the Plasma Membrane and Its Proteome from Cells in Suspension. Methods Mol Biol 1722:79-90
Ostrand-Rosenberg, Suzanne; Fenselau, Catherine (2018) Myeloid-Derived Suppressor Cells: Immune-Suppressive Cells That Impair Antitumor Immunity and Are Sculpted by Their Environment. J Immunol 200:422-431
Aebersold, Ruedi; Agar, Jeffrey N; Amster, I Jonathan et al. (2018) How many human proteoforms are there? Nat Chem Biol 14:206-214
Ostrand-Rosenberg, Suzanne (2018) Myeloid derived-suppressor cells: their role in cancer and obesity. Curr Opin Immunol 51:68-75
Adams, Katherine R; Chauhan, Sitara; Patel, Divya B et al. (2018) Ubiquitin Conjugation Probed by Inflammation in Myeloid-Derived Suppressor Cell Extracellular Vesicles. J Proteome Res 17:315-324
Chen, Dapeng; Gomes, Fabio; Abeykoon, Dulith et al. (2018) Top-Down Analysis of Branched Proteins Using Mass Spectrometry. Anal Chem 90:4032-4038
Geis-Asteggiante, LucĂ­a; Belew, Ashton T; Clements, Virginia K et al. (2018) Differential Content of Proteins, mRNAs, and miRNAs Suggests that MDSC and Their Exosomes May Mediate Distinct Immune Suppressive Functions. J Proteome Res 17:486-498
Horn, Lucas A; Long, Tiha M; Atkinson, Ryan et al. (2018) Soluble CD80 Protein Delays Tumor Growth and Promotes Tumor-Infiltrating Lymphocytes. Cancer Immunol Res 6:59-68
Singh, Rajesh K; Kazansky, Yaniv; Wathieu, Donald et al. (2017) Hydrophobic Patch of Ubiquitin is Important for its Optimal Activation by Ubiquitin Activating Enzyme E1. Anal Chem 89:7852-7860
Chauhan, Sitara; Danielson, Steven; Clements, Virginia et al. (2017) Surface Glycoproteins of Exosomes Shed by Myeloid-Derived Suppressor Cells Contribute to Function. J Proteome Res 16:238-246

Showing the most recent 10 out of 115 publications