Quantitative Proteomics Analysis Integrated with Microarray Data Reveals That Extracellular Matrix Proteins, Catenins, and P53 Binding Protein 1 Are Important for Chemotherapy Response in Ovarian Cancers

Abstract

Chemotherapy with carboplatin and paclitaxel is the standard treatment for ovarian cancer patients. Although most patients initially respond to this treatment, few are cured. Resistance to chemotherapy is the major cause of treatment failure. We applied a quantitative proteomic approach based on ICAT/MS/MS technology to analyze tissues harvested at primary debulking surgery before the initiation of combination chemotherapy in order to identify potential naive or intrinsic chemotherapy response proteins in ovarian cancers. We identified 44 proteins that are overexpressed, and 34 proteins that are underexpressed in the chemosensitive tissue compared to the chemoresistant tissue. The overexpressed proteins identified in the chemoresistant tissue include 10 proteins (25.6%) belonging to the extracellular matrix (ECM), including decorin, versican, basigin (CD147), fibulin-1, extracellular matrix protein 1, biglycan, fibronectin 1, dermatopontin, alpha-cardiac actin (smooth muscle actin), and an EGF-containing fibulin-like extracellular matrix protein 1. Interesting proteins identified as overexpressed in the chemosensitive tissue include gamma-catenin (junction plakoglobin) and delta-catenin, tumor suppressor p53-binding protein 1 (53BP1), insulin-like growth factor-binding protein 2 (IGFBP2), proliferating cell nuclear antigen (PCNA), annexin A11, and 53 kDa selenium binding protein 1. Integrative analysis with expression profiling data of eight chemoresistant tissues and 13 chemosensitive tissues revealed that 16 proteins showed consistent changes at both the protein and the RNA levels. These include P53 binding protein 1, catenin delta 1 and plakoglobin, EGF-containing fibulin-like extracellular matrix protein 1 and voltage-dependent anion-selective channel protein 1. Our results suggest that chemotherapy response may be determined by multiple and complex system properties involving extracellular-matrix, cell adhesion and junction proteins.

53BP1 inhibits the migration and regulates the chemotherapy resistance of ovarian cancer cells

“…However, a consensus on the effects of 53BP1 on cellular responses to chemotherapeutic agents has yet to be reached, with multiple studies having demonstrated increased or decreased drug sensitivity with 53BP1 overexpression (11,32,33). These conflicting reports suggest that the association between 53BP1 and chemosensitivity may be more complex than previously assumed.…”

TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer

“…paclitaxel-resistant and sensitive-cell models 26,27 or chemoresistant and chemosensitive tissues from ovarian cancer patients 28 by different proteomic techniques, such as 2-dimensional electrophoresis (2DE) or difference gel electrophoresis (DIGE) coupled with mass spectrometry, and isotope-coded affinity tags (ICAT) labeling combined with LC-MS proteomic analyses. In the present study, we identified 356 proteins differentially expressed at a 1.5-fold or higher intensity between a paclitaxel-resistant www.tandfonline.comSKOV3-TR30 and a paclitaxel-sensitive SKOV3 cell line using LC-MS/MS label-free quantitative proteomic analyses with spectral counting strategy.…”

Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response

“…Genes encoding ECM components are upregulated in tumors that are resistant to anticancer treatments (Pan et al, 2009;Sherman-Baust et al, 2003), and tumor cell adhesion to the ECM increases resistance to anticancer agents (Streuli and Gilmore, 1999). Moreover, remodeling of the ECM in response to irradiation is suggested to contribute to genomic instability and carcinogenesis induced by ionizing radiation (Barcellos-Hoff, 1998).…”