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Synergistic suppression of apoptosis in salivary acinar cells by IGF1 and EGF
K H Limesand1, K A Barzen, D O Quissell
1Department of Pathology, School of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Abstract:
Tissue homeostasis requires balancing cell proliferation and programmed cell death. IGF1 significantly suppressed etoposide-induced apoptosis, measured by caspase 3 activation and quantitation of cellular subG(1) DNA content, in rat parotid salivary acinar cells (C5). Transduction of C5 cells with an adenovirus expressing a constitutively activated mutant of Akt-suppressed etoposide-induced apoptosis, whereas a kinase-inactive mutant of Akt suppressed the protective effect of IGF1. IGF1 also suppressed apoptosis induced by taxol and brefeldin A. EGF was unable to suppress apoptosis induced by etoposide, but was able to synergize with IGF1 to further suppress caspase 3 activation and DNA cleavage after etoposide treatment. The catalytic activity of Akt was significantly higher following stimulation with both growth factors compared to stimulation with IGF1 or EGF alone. These results suggest that a threshold of activated Akt is required for suppression of apoptosis and the cooperative action of growth factors in regulating salivary gland homeostasis.
Insights
Insulin-like growth factor 1 (IGF1) and Akt signaling protect salivary acinar cells from apoptosis. Cooperative action of IGF1 and EGF requires a threshold of activated Akt for regulating salivary gland homeostasis.
Area of Science:
- Cell Biology
- Molecular Biology
- Physiology
Background:
- Tissue homeostasis relies on a balance between cell proliferation and programmed cell death (apoptosis).
- Growth factors play crucial roles in regulating cellular survival and death pathways.
- Salivary gland function and homeostasis are critical for oral health.
Purpose of the Study:
- To investigate the role of Insulin-like Growth Factor 1 (IGF1) and Akt signaling in regulating apoptosis in rat parotid salivary acinar cells.
- To determine the involvement of Akt kinase activity in the anti-apoptotic effects of IGF1.
- To explore the synergistic effects of IGF1 and Epidermal Growth Factor (EGF) on apoptosis regulation.
Main Methods:
- Primary rat parotid salivary acinar cells (C5) were treated with apoptosis-inducing agents (etoposide, taxol, brefeldin A).
- Apoptosis was assessed by measuring caspase-3 activation and subG1 DNA content.
- Cells were transduced with adenoviruses expressing wild-type, constitutively active, or kinase-inactive Akt mutants.
- Cells were stimulated with IGF1 and/or EGF, and Akt catalytic activity was measured.
Main Results:
- IGF1 significantly suppressed etoposide-induced apoptosis in C5 cells.
- Constitutively active Akt mimicked the anti-apoptotic effect of IGF1, while kinase-inactive Akt blocked IGF1's protective effect.
- IGF1 also inhibited apoptosis induced by taxol and brefeldin A.
- EGF alone did not suppress etoposide-induced apoptosis but synergized with IGF1 to enhance apoptosis suppression.
- Combined IGF1 and EGF stimulation resulted in significantly higher Akt catalytic activity compared to individual growth factor stimulation.
Conclusions:
- A threshold level of activated Akt is necessary for the suppression of apoptosis in salivary acinar cells.
- IGF1 exerts its protective effect against apoptosis through Akt activation.
- Cooperative signaling between IGF1 and EGF, mediated by Akt, is important for maintaining salivary gland homeostasis.
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