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Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway
Ya-Wei Qiang1, Eugene Kopantzev, Stuart Rudikoff
1Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Abstract:
In multiple myeloma cells, insulinlike growth factor-I (IGF-I) activates 2 distinct signaling pathways, mitogen-activated protein kinase (MAPK) and phosphoinositol 3-kinase (PI-3K), leading to both proliferative and antiapoptotic effects. However, it is unclear through which of these cascades IGF-I regulates these different responses. The present studies identify a series of downstream targets in the PI-3K pathway, including glycogen synthase kinase-3beta, p70S6 kinase, and the 3 members of the Forkhead family of transcription factors. The contribution of the MAPK and PI-3K pathways and, where possible, individual elements to proliferation and apoptosis was evaluated by means of a series of specific kinase inhibitors. Both processes were regulated almost exclusively by the PI-3K pathway, with only minor contributions associated with the MAPK cascade. Within the PI-3K cascade, inhibition of p70S6 kinase led to significant decreases in proliferation and protection from apoptosis. Activation of p70S6 kinase could also be prevented by MAPK inhibitors, indicating regulation by both pathways. The Forkhead transcription factor FKHRL1 was observed to provide a dual effect in that phosphorylation upon IGF-I treatment resulted in a loss of ability to inhibit proliferation and induce apoptosis. The PI-3K pathway was additionally shown to exhibit cross-talk and to regulate the MAPK cascade, as inhibition of PI-3K prevented activation of Mek1/2 and other downstream MAPK elements. These results define important elements in IGF-I regulation of myeloma cell growth and provide biological correlates critical to an understanding of growth-factor modulation of proliferation and apoptosis.
Insights
Insulin-like growth factor-I (IGF-I) primarily uses the phosphoinositol 3-kinase (PI-3K) pathway to control multiple myeloma cell proliferation and apoptosis, with some cross-talk from the mitogen-activated protein kinase (MAPK) pathway.
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Research
Background:
- Insulin-like growth factor-I (IGF-I) influences multiple myeloma cell growth through distinct signaling pathways.
- The precise roles of the mitogen-activated protein kinase (MAPK) and phosphoinositol 3-kinase (PI-3K) pathways in mediating IGF-I's proliferative and antiapoptotic effects remain unclear.
Purpose of the Study:
- To elucidate the specific roles of the MAPK and PI-3K pathways in IGF-I-mediated proliferation and apoptosis in multiple myeloma cells.
- To identify downstream targets within these signaling cascades that contribute to cellular responses.
Main Methods:
- Utilized specific kinase inhibitors to evaluate the contributions of MAPK and PI-3K pathways to proliferation and apoptosis.
- Investigated downstream targets of the PI-3K pathway, including glycogen synthase kinase-3beta, p70S6 kinase, and Forkhead transcription factors.
Main Results:
- The PI-3K pathway predominantly regulates myeloma cell proliferation and apoptosis, with minor involvement of the MAPK pathway.
- Inhibition of p70S6 kinase within the PI-3K pathway significantly reduced proliferation and protected against apoptosis.
- Cross-talk was observed, with MAPK inhibitors affecting p70S6 kinase activation and PI-3K inhibition impacting MAPK cascade elements like Mek1/2.
Conclusions:
- IGF-I primarily utilizes the PI-3K pathway to regulate multiple myeloma cell proliferation and apoptosis.
- The Forkhead transcription factor FKHRL1 plays a dual role, with its phosphorylation by IGF-I diminishing its inhibitory effects on proliferation and apoptosis.
- These findings provide critical insights into growth factor signaling in myeloma cell biology and potential therapeutic targets.