Mechanisms regulating the constitutive activation of the extracellular signal-regulated kinase (ERK) signaling pathway in ovarian cancer and the effect of ribonucleic acid interference for ERK1/2 on cancer cell proliferation.

Mechanisms regulating the constitutive activation of the extracellular signal-regulated kinase (ERK) signaling pathway in ovarian cancer and the effect of ribonucleic acid interference for ERK1/2 on cancer cell proliferation. Steinmetz, R., Wagoner, H., A., Zeng, P., Hammond, J., R., Hannon, T., S., Meyers, J., L., & Pescovitz, O., H. Mol Endocrinol, 18(10):2570-2582, 2004.

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The ERK1/2 MAPK pathway is a critical signaling system that mediates ligand-stimulated signals for the induction of cell proliferation, differentiation, and cell survival. Studies have shown that this pathway is constitutively active in several human malignancies and may be involved in the pathogenesis of these tumors. In the present study we examined the ERK1/2 pathway in cell lines derived from epithelial and granulosa cell tumors, two distinct forms of ovarian cancer. We show that ERK1 and ERK2 are constitutively active and that this activation results from both MAPK kinase-dependent and independent mechanisms and is correlated with elevated BRAF expression. MAPK phosphatase 1 (MKP-1) expression, which is involved in ERK1/2 deactivation, is down-regulated in the cancer cells, thus further contributing to ERK hyperactivity in these cells. Treatment of these cancer cell lines with the proteasome inhibitor ZLLF-CHO increased MKP-1 but not MKP-2 expression and decreased ERK1/2 phosphorylation. More importantly, silencing of ERK1/2 protein expression using RNA interference led to the complete suppression of tumor cell proliferation. These results provide evidence that the ERK pathway plays a major role in ovarian cancer pathogenesis and that down-regulation of this master signaling pathway is highly effective for the inhibition of ovarian tumor growth.

@article{
 title = {Mechanisms regulating the constitutive activation of the extracellular signal-regulated kinase (ERK) signaling pathway in ovarian cancer and the effect of ribonucleic acid interference for ERK1/2 on cancer cell proliferation.},
 type = {article},
 year = {2004},
 identifiers = {[object Object]},
 keywords = {Cell Division; Enzyme Activation; Extracellular Si,genetics/pathology; RNA Interference,genetics/physiology; Mitogen-Activated Protein Ki,genetics; Mitogen-Activated Protein Kinase 3,genetics; Ovarian Neoplasms,metabolism; Female; Humans; MAP Kinase Signaling},
 pages = {2570-2582},
 volume = {18},
 websites = {http://dx.doi.org/10.1210/me.2004-0082},
 institution = {Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana 46202, USA. rsteinme@iupui.edu},
 id = {8379bf8a-186c-3857-bd70-345b742c0ec0},
 created = {2012-04-04T15:37:38.000Z},
 file_attached = {false},
 profile_id = {00fd71da-e805-3e9b-bd6d-ce1da66adfce},
 group_id = {65b20e96-92ca-3d76-a4e9-a84ba22c682d},
 last_modified = {2012-04-04T15:47:00.000Z},
 read = {false},
 starred = {false},
 authored = {false},
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 citation_key = {Steinmetz2004},
 source_type = {article},
 abstract = {The ERK1/2 MAPK pathway is a critical signaling system that mediates
ligand-stimulated signals for the induction of cell proliferation,
differentiation, and cell survival. Studies have shown that this
pathway is constitutively active in several human malignancies and
may be involved in the pathogenesis of these tumors. In the present
study we examined the ERK1/2 pathway in cell lines derived from epithelial
and granulosa cell tumors, two distinct forms of ovarian cancer.
We show that ERK1 and ERK2 are constitutively active and that this
activation results from both MAPK kinase-dependent and independent
mechanisms and is correlated with elevated BRAF expression. MAPK
phosphatase 1 (MKP-1) expression, which is involved in ERK1/2 deactivation,
is down-regulated in the cancer cells, thus further contributing
to ERK hyperactivity in these cells. Treatment of these cancer cell
lines with the proteasome inhibitor ZLLF-CHO increased MKP-1 but
not MKP-2 expression and decreased ERK1/2 phosphorylation. More importantly,
silencing of ERK1/2 protein expression using RNA interference led
to the complete suppression of tumor cell proliferation. These results
provide evidence that the ERK pathway plays a major role in ovarian
cancer pathogenesis and that down-regulation of this master signaling
pathway is highly effective for the inhibition of ovarian tumor growth.},
 bibtype = {article},
 author = {Steinmetz, Rosemary and Wagoner, Heather A and Zeng, Pingyu and Hammond, Jessica R and Hannon, Tamara S and Meyers, Justin L and Pescovitz, Ora H},
 journal = {Mol Endocrinol},
 number = {10}
}

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