Identification of CD44 as a Surface Biomarker for Drug Resistance by Surface Proteome Signature Technology

Abstract

We developed surface proteome signatures (SPS) for identification of new biomarkers playing a role in cancer drug resistance. SPS compares surface antigen expression of different cell lines by immunocytochemistry of a phage display antibody library directed to surface antigens of HT1080 fibrosarcoma cells. We applied SPS to compare the surface proteomes of two epithelial derived cancer cell lines, MCF7 and NCI/ADR-RES, which is drug resistant because of overexpression of the P-glycoprotein (P-gp) drug efflux pump. Surface proteomic profiling identified CD44 as an additional biomarker that distinguishes between these two cell lines. CD44 immunohistochemistry can distinguish between tumors derived from these lines and predict tumor response to doxorubicin in vivo. We further show that CD44 plays a role in drug resistance, independently of P-gp, in NCI/ADR-RES cells and increases expression of the antiapoptotic protein Bcl-xL. Our findings illustrate the utility of SPS to distinguish between cancer cell lines and their derived tumors and identify novel biomarkers involved in drug resistance. Mol Cancer Res; 9(5); 637-47. Ó2011 AACR.

Carbonic anhydrase XII is a new therapeutic target to overcome chemoresistance in cancer cells

“…Until now, only few studies have analyzed the surfaceome of chemoresistant cells [8, 9]. These studies have identified proteins that were overexpressed in MDR cells, such as CD44 [8], dihydropyridine receptor alpha 2 and laminin subunit alpha 5 [9].…”

Targeting CD44 by CRISPR-Cas9 in Multi-Drug Resistant Osteosarcoma Cells

“…CD44 expression is also considered as an important biomarker to predict the sensitivity of chemotherapy in ovarian cancer, fibrosarcoma and Gastric cancer [8,46,48]. And CD44 abnormal expression can directly affect the emergence of drug-resistant phenotype [49,50].…”

CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

“…Thus, for nanoparticle-based immunotargeting against tumor antigens which overexpressed on the cancer cell surface, the antibodies were conjugated with nanoparticulate drug delivery systems to provide immunoconjugates that conferred the greater selectivity to the drug and the higher uptake by means of receptormediated endocytosis [38]. CD44 exhibits as a potential biomarker for drug resistance [23]. An immunohistochemical analysis of breast cancer tissue from untreated female patients demonstrated a statistical correlation between CD44 and P-gp expression [45].…”

“…CD44 is overexpressed in breast cancer stem cells and MDR breast cancer cells [22][23][24]. There is strong evidence that CD44 is involved in inducing transcriptional up-regulation of the MDR1 gene to promote MDR [25,26].…”

“…Misra et al [27] implicated that soluble CD44 antibody reverse this increase of P-gp expression to sensitize the cells to DOX treatment. Furthermore, it is shown that CD44 plays a role in drug resistance via its increase of expression of the antiapoptotic protein Bcl-xL [23]. On the other hand, CD44 monoclonal antibody (McAb) can markedly inhibit proliferation and stimulate apoptosis in different types of cancer [28,29].…”