GBP1 overexpression is associated with a paclitaxel resistance phenotype

Abstract

In the search for novel genes involved in the paclitaxel resistance phenotype, prior studies of gene expression in paclitaxel-resistant cell lines and their paired drug-sensitive parental lines using high-density Affymetrix GeneChip arrays identified guanylate-binding protein 1 (GBP1) gene as an overexpressed transcript. The GBP1 gene encodes a large GTPase that is induced by interferon gamma (IFN-gamma) in a variety of eukaryotic cells. In this report we characterize GBP1 and demonstrate that GBP1 expression is consistently upregulated in 7 of 8 paclitaxel or doxorubicin-resistant human cancer cell lines as compared to its expression in the relevant drug-sensitive parental lines. Analysis of GBP1 expression using the Cancer Profiling Array showed that GBP1 is ubiquitously expressed with no significant difference in expression levels between normal and tumor tissue. Parallel analysis of the Cancer Cell Line Profiling Array determined that GBP1 expression in a majority of cell lines derived from human tumors of different tissue origin was induced to variable levels following exposure to multiple stress agents including paclitaxel and doxorubicin. Importantly, stable expression of a GBP1 transgene in the paclitaxel-sensitive ovarian cancer cell line OVCAR8 was sufficient to confer moderate paclitaxel resistance. Our data suggest that increased expression of the GBP1 gene may play an important role in the development of multi-drug resistance (MDR).

Gene expression profiling of the androgen independent prostate cancer cells demonstrates complex mechanisms mediating resistance to docetaxel

“…The MTT assay showed (RELB, NFκB2, IL1, FGF1, FGF5, EGR1), p53 signaling pathway (CyclinG 2 , IGFBP3, SERPIN1), Toll receptor (TLR4, NFκB2, PTGS2, TNFAIP3, RELB), TGFbeta (ID2, FKBP1B), a closely associated coagulation and plasminogen activation cascades (F3, PLAUR, C3, SERPINE1, MMP13, SERPINB2) and steroid hormone biosynthesis (CYP1B1, ALDH3A2). A set of genes with an established role in multidrug and/or taxane specific resistance was also found and included GBP1, 6 Serpin1 and SerpinB2, CXCL5, AKAP12, 7 LAMC2, 8 as well as TGFβI 9 all of which were constitutively downregulated in PC-3 cell clones. Exception was a constitutively upregulated tubulin α1, a member of the tubulin family of microtubule proteins, the target for docetaxel binding and a well established taxane resistance mediator.…”

“…These experimental conditions were sought to help a prominent mediator of paclitaxel resistance. 6 We found that the ectopic overexpression of GBP1 using cDNA plasmid constructs notably increases docetaxel sensitivity. Altogether, our studies suggested existence of different, complex and likely complementary molecular mechanisms mediating resistance to docetaxel and suggested new potential target leads for future investigations.…”

“…Similarly, an upregulation of GBP1 expression important in facilitating resistance to paclitaxel 6 was also not observed. To investigate this trend we evaluated significance of the constitutive downregulation of GBP1 in PC-3 cells.…”

Guanylate Binding Protein 1–Mediated Interaction of T Cell Antigen Receptor Signaling with the Cytoskeleton

“…The only cellular interaction partner of GBP-1 known so far is b-IIITubulin (14). This points to interaction of GBP-1 with structural proteins and suggests that overexpression of GBP-1 in paclitaxel-resistant cells is directly associated to the therapeutic failure of this antimitotic drug in certain tumors (15).…”

Extensive Characterization of IFN-Induced GTPases mGBP1 to mGBP10 Involved in Host Defense

“…hGBP1 also has been shown to negatively regulate expression of matrix metalloproteinase 1 in endothelial cells, leading to reduced invasive capabilities of the cells into collagen I matrices (22). Additionally, hGBP1 expression has been associated with paclitaxel resistance in ovarian cancer cell lines (23).…”