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Phosphatidylinositol 3-kinase-dependent, MEK- independent proliferation in response to CaR activation
Tim R Bilderback1, Fred Lee, Nelly Auersperg
1Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, Oregon 97201-3098, USA.
Abstract:
Although ovarian surface epithelial (OSE) cells are responsible for the majority of ovarian tumors, we know relatively little about the pathway(s) that is responsible for regulating their proliferation. We found that phosphatidylinositol 3-kinase (PI3K) is activated in OSE cells in response to elevated extracellular calcium, and the PI3K inhibitors wortmannin and LY-294002 inhibited extracellular signal-regulated kinase (ERK) activation by approximately 75%, similar to effects of the mitogen-activated protein kinase/ERK kinase inhibitor PD-98059. However, in assays of proliferation, we found that PD-98059 inhibited proliferation by approximately 50%, whereas wortmannin inhibited >90% of the proliferative response to elevated calcium. Expression of a dominant negative PI3K totally inhibited ERK activation in response to calcium. These results demonstrate that ERK activation cannot account for the full proliferative effect of elevated calcium in OSE cells and suggest the presence of an ERK-independent, PI3K-dependent component in the proliferative response.
Insights
Elevated calcium activates phosphatidylinositol 3-kinase (PI3K) in ovarian cells, driving proliferation independently of extracellular signal-regulated kinase (ERK) signaling. This PI3K pathway is crucial for ovarian surface epithelial cell growth.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Ovarian surface epithelial (OSE) cells are implicated in most ovarian tumors.
- Regulatory pathways controlling OSE cell proliferation remain poorly understood.
Purpose of the Study:
- To investigate the role of phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) in calcium-induced proliferation of OSE cells.
Main Methods:
- Treatment of OSE cells with elevated extracellular calcium.
- Inhibition of PI3K and ERK pathways using specific inhibitors (wortmannin, LY-294002, PD-98059).
- Assessment of ERK activation and cell proliferation assays.
- Expression of dominant-negative PI3K.
Main Results:
- Elevated calcium activates PI3K in OSE cells.
- PI3K inhibition significantly reduced calcium-induced proliferation (>90%), while ERK inhibition had a lesser effect (~50%).
- PI3K is essential for ERK activation in response to calcium.
Conclusions:
- Calcium-induced OSE cell proliferation involves both ERK-dependent and ERK-independent pathways.
- The ERK-independent pathway is critically dependent on PI3K activation.
- PI3K plays a dominant role in regulating calcium-mediated OSE cell proliferation.