Ovarian cancer

Ozols, Robert F.

doi:10.1002/ssu.2980060607

Cited by 28 publications

(30 citation statements)

References 65 publications

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“…8A and data not shown). Moreover, HSulf-1 re-expression enhanced the sensitivity of these cells to a number of pro-apoptotic stimuli, including cisplatin, which is widely used to treat ovarian cancer (55), and staurosporine, a broadly active kinase inhibitor that is widely employed as a stimulus of the mitochondrial apoptotic pathway (44,56). These results are consistent with previous studies (57,58) demonstrating ERK phosphorylation and ability of the Mek1/2 inhibitor PD98059 to modulate cisplatin sensitivity in ovarian cancer cells.…”

Section: Discussionsupporting

confidence: 90%

Loss of HSulf-1 Up-regulates Heparin-binding Growth Factor Signaling in Cancer

Lai

Chien

Staub

et al. 2003

Journal of Biological Chemistry

239

325

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Emerging data suggest that signaling by heparinbinding growth factors is influenced by the sulfation state of N-acetylglucosamine residues of heparan sulfate proteoglycans (HSPGs). Here we report that the recently identified protein HSulf-1, a heparin-degrading endosulfatase, encodes a cell surface-associated enzyme that diminishes sulfation of cell surface HSPGs. The message encoding this enzyme is readily detectable in a variety of normal tissues, including normal ovarian surface epithelial cells, but is undetectable in 5 of 7 ovarian carcinoma cell lines and markedly diminished or undetectable in ϳ75% of ovarian cancers. Similar down-regulation is also observed in breast, pancreatic, renal cells, and hepatocellular carcinoma lines. Re-expression of HSulf-1 in ovarian cancer cell lines resulted in diminished HSPG sulfation, diminished phosphorylation of receptor tyrosine kinases that require sulfated HSPGs as co-receptors for their cognate ligands, and diminished downstream signaling through the extracellular signal-regulated kinase pathway after treatment with fibroblast growth factor-2 or heparin-binding epidermal growth factor. Consistent with these changes, HSulf-1 re-expression resulted in reduced proliferation as well as sensitivity to induction of apoptosis by the broad spectrum kinase inhibitor staurosporine and the chemotherapeutic agent cisplatin. Collectively, these observations provide evidence that HSulf-1 modulates signaling by heparin-binding growth factors, and HSulf-1 downregulation represents a novel mechanism by which cancer cells can enhance growth factor signaling.

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Section: Discussionsupporting

confidence: 90%

Loss of HSulf-1 Up-regulates Heparin-binding Growth Factor Signaling in Cancer

Lai

Chien

Staub

et al. 2003

Journal of Biological Chemistry

239

325

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“…At present, a combination of paclitaxel with cisplatin is considered to be the best chemotherapy regimen for this aggressive cancer disease (Rowinsky et al, 1991;McGuire et al, 1995). However, the overall 5-year survival rate following such treatment is still unsatisfactory (Ozols, 1995). Thus, development of alternative therapeutic strategies is desirable in the management of this fatal disease.…”

Section: Introductionmentioning

confidence: 99%

Critical role of both retinoid nuclear receptors and retinoid-X-receptors in mediating growth inhibition of ovarian cancer cells by all-trans retinoic acid

Zhang

Zhu

et al. 1998

Oncogene

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“…In studies where transfected cDNAs were used to compare cell populations that differed in the single variable of glutathione S-transferase expression, the recombinant rat 1-1 isozyme conferred as much as 3-fold resistance to chlorambucil in mouse fibroblasts (10), and this fold resistance overlaps the fold resistance seen in clinical studies of nitrogen mustard resistance (11,12). Consistent with the observed drug resistance, glutathione S-transferases have been shown to catalyze the conjugation of the nitrogen mustards chlorambucil and melphalan to glutathione (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Forced evolution of glutathione S-transferase to create a more efficient drug detoxication enzyme.

Gulick

Fahl

1995

Proc. Natl. Acad. Sci. U.S.A.

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Glutathione S-transferases (EC 2.5.1.18) in mammalian cells catalyze the conjugation, and thus, the detoxication of a structurally diverse group of electrophilic environmental carcinogens and alkylating drugs, including the antineoplastic nitrogen mustards. We proposed that structural alteration of the nonspecific electrophile-binding site would produce mutant enzymes with increased efficiency for detoxication of a single drug and that these mutants could serve as useful somatic transgenes to protect healthy human cells against single alkylating agents used in cancer chemotherapy protocols. Random mutagenesis of three regions (residues 9-14, 102-112, and 210-220), which together compose the glutathione S-transferase electrophile-binding site, followed by selection ofEscherichia coli expressing the enzyme library with the nitrogen mustard mechlorethamine (20-500 ,uM), yielded mutant enzymes that showed significant improvement in catalytic efficiency for mechlorethamine conjugation (up to 15-fold increase in ka,t and up to 6-fold increase in kct/Km) and that confer up to 31-fold resistance, which is 9-fold greater drug resistance than that conferred by the wild-type enzyme. The results suggest a general strategy for modification of drug-and carcinogen-metabolizing enzymes to achieve desired resistance in both prokaryotic and eukaryotic plant and animal cells.The glutathione S-transferases (EC 2.5.1.18) are a family of enzymes that are responsible for the detoxication of a broad class of electrophiles. In both prokaryotic and eukaryotic cells, these enzymes have been shown to catalyze the conjugation of the tripeptide glutathione to a variety of compounds, resulting in products that are generally less reactive (1-3). High levels of expression of several related glutathione S-transferase isozymes enable these enzymes to protect the cell from numerous structurally diverse electrophiles present in our environment (4-6) and used in cancer chemotherapy (1, 2).Several reports have shown that chronic treatment of cultured cells (7,8) or clinical tumors (9) with alkylating agents results in resistant subpopulations of cells that express alpha class glutathione S-transferases at levels higher than those in the sensitive parental populations. In studies where transfected cDNAs were used to compare cell populations that differed in the single variable of glutathione S-transferase expression, the recombinant rat 1-1 isozyme conferred as much as 3-fold resistance to chlorambucil in mouse fibroblasts (10), and this fold resistance overlaps the fold resistance seen in clinical studies of nitrogen mustard resistance (11,12). Consistent with the observed drug resistance, glutathione S-transferases have been shown to catalyze the conjugation of the nitrogen mustards chlorambucil and melphalan to glutathione (13)(14)(15).Each subunit of a glutathione S-transferase dimer contains an independent active site composed of a G site for binding glutathione and an H site for binding hydrophobic electrophiles (2). Each subunit contain...

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Ovarian cancer

Cited by 28 publications

References 65 publications

Loss of HSulf-1 Up-regulates Heparin-binding Growth Factor Signaling in Cancer

Loss of HSulf-1 Up-regulates Heparin-binding Growth Factor Signaling in Cancer

Critical role of both retinoid nuclear receptors and retinoid-X-receptors in mediating growth inhibition of ovarian cancer cells by all-trans retinoic acid

Forced evolution of glutathione S-transferase to create a more efficient drug detoxication enzyme.

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