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

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.

A novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN sustains high growth of breast cancer cells

“…In this text, we confirmed the data (data not shown). Activation of ERK1/2 and overexpression of 5-LOX are frequently observed in various human tumors [36,37] . Thus, we conclude that p-ERK1/2 activates 5-LOX in breast cancer cells.…”

Chemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2

“…This observation however seems to be consistent with the mechanism of drug-resistant action in ovarian cancer. Several studies have demonstrated that ERK1/2 activity is elevated in human ovarian tumours, and its activation conferred resistance to chemotherapeutic agents (Pan et al, 2002;Steinmetz et al, 2004;Lee et al, 2007). Cisplatin, another platinum-based chemotherapy, has also been found recently to enhance ovarian cancer cell resistance to apoptosis through activation of ERK1/2 (Lee et al, 2007).…”

Hyaluronan-CD44 Interaction with IQGAP1 Promotes Cdc42 and ERK Signaling, Leading to Actin Binding, Elk-1/Estrogen Receptor Transcriptional Activation, and Ovarian Cancer Progression

“…The MAPKs ERK1 and ERK2 are ubiquitous protein kinases that transmit and integrate cell-surface signals by phosphorylating target proteins throughout the cell. In particular, ERK signaling is closely associated with ovarian cancer progression (55)(56)(57). Therefore, an understanding of how ERK activation is regulated will provide important insight into the disease mechanisms related to cancer progression.…”