Cancer Drug Targets Identification

Membrane proteins are common drug and antibody targets (86). The three postgen-omics mechanism-based cancer drugs and antibody, Gleevec, Herceptin, and Iressa, are all targeted against membrane proteins (87-89). These therapeutic successes have led to efforts to adopt cutting-edge technology such as mass-spectrometry-based proteomics to speed up the traditional one-molecule-at-a-time-based approach for cancer therapeutic targets discovery. The most recent achievement is potential therapeutic targets identification by a comprehensive proteomic analysis using the breast cancer cell membrane (90). In this study, tandem mass spectra were searched against a comprehensive database using the SEQUEST search program, resulting in the identification of tumor-cell-specific plasma-membrane-associated novel proteins. Among them are many highly abundant proteins such as her2/neu and rare unique proteins such as BCMP101, showing a wide dynamic range of breast cancer membrane proteins. Three unique proteins, BCMP11/ hAG3, BCMP101, and BCMP84, were characterized further and found significant expression in clinical breast tumor tissues. Among them, BCMP11/hAG3 was found to have potential localization in secretory organelles, interacts with C4.4A, and represents a potential autocrine receptor for BCMP11. BCMP101 has highly restricted expression in breast cancer with localization in the plasma membrane and interaction with a-1-catenin, through which its potential role of blocking tumor suppression can be achieved. BCMP84 is particularly interesting in terms of tumor-specific translocation from cytosol to plasma membrane in breast cancer. This translocation ofBCMP84 is regulated in a calcium-dependent manner through interaction with nucleobindin, which has strong association with Ga proteins. These findings suggests a possible role for BCMP84 in G-protein-coupled signal transduction events and further showcase the strength of mass-spectrometry-based prote-omic in detecting cancer-associated protein translocation, an event that cannot be detected at the level of transcriptome.

Stathmin (Op18), a major tubulin regulatory protein in leukemia, has been discovered by 2D electrophoresis (2DE) mass-spectrometry-based proteomics as a potential target to inhibit the proliferation of leukemia cell (91,92). Stathmin is a substrate of several kinase families; thus, it is a phosphorylation-responsive regulator of multiple signal transduction pathways in microtubule dynamics. The study showed a significant overexpression of the phosphorylated form of Stathmin in childhood leukemia (93). The important role of Stathmin in regulating leukemia cell proliferation and differentiation was further confirmed by an in vivo functional study (92). This study emphasized the unsurpassed power of mass-spectrometry-based proteomics to identify posttranslational modified proteins as a cancer therapeutic target because genomics lack the ability to detect protein posttranslational modifications.

These studies suggest that application of more advanced methodologies such as multidimensional protein identification technology or isotope-coded affinity tagging as well as new MS technologies, including linear ion trap and TOF-TOF instruments, could enable the direct identification of proteins of lower abundance and posttranslational modifications for the discovery of potential targets for cancer therapy.

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