Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain
<p>Abstract</p> <p>Background</p> <p>AMP-activated protein kinase (AMPK) is a known physiological cellular energy sensor and becomes phosphorylated at Thr-172 in response to changes in cellular ATP levels. Activated AMPK acts as either an inducer or suppressor of apopto...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2008-05-01
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| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/7/1/37 |
| _version_ | 1818825251257057280 |
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| author | Chiles Thomas C Blair Derek Marsh Jeremy Mulrooney Tiernan J Mukherjee Purna Seyfried Thomas N |
| author_facet | Chiles Thomas C Blair Derek Marsh Jeremy Mulrooney Tiernan J Mukherjee Purna Seyfried Thomas N |
| author_sort | Chiles Thomas C |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>AMP-activated protein kinase (AMPK) is a known physiological cellular energy sensor and becomes phosphorylated at Thr-172 in response to changes in cellular ATP levels. Activated AMPK acts as either an inducer or suppressor of apoptosis depending on the severity of energy stress and the presence or absence of certain functional tumor suppressor genes.</p> <p>Results</p> <p>Here we show that energy stress differentially affects AMPK phosphorylation and cell-death in brain tumor tissue and in tissue from contra-lateral normal brain. We compared TSC2 deficient CT-2A mouse astrocytoma cells with syngeneic normal astrocytes that were grown under identical condition <it>in vitro</it>. Energy stress induced by glucose withdrawal or addition of 2-deoxyglucose caused more ATP depletion, AMPK phosphorylation and apoptosis in CT-2A cells than in the normal astrocytes. Under normal energy conditions pharmacological stimulation of AMPK caused apoptosis in CT-2A cells but not in astrocytes. TSC2 siRNA treated astrocytes are hypersensitive to apoptosis induced by energy stress compared to control cells. AMPK phosphorylation and apoptosis were also greater in the CT-2A tumor tissue than in the normal brain tissue following implementation of dietary energy restriction. Inefficient mTOR and TSC2 signaling, downstream of AMPK, is responsible for CT-2A cell-death, while functional LKB1 may protect normal brain cells under energy stress.</p> <p>Conclusion</p> <p>Together these data demonstrates that AMPK phosphorylation induces apoptosis in mouse astrocytoma but may protect normal brain cells from apoptosis under similar energy stress condition. Therefore, using activator of AMPK along with glycolysis inhibitor could be a potential therapeutic approach for TSC2 deficient human malignant astrocytoma.</p> |
| first_indexed | 2024-12-19T00:08:48Z |
| format | Article |
| id | doaj.art-eabfd986bd9b440f99e7fe7c7e26db69 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-19T00:08:48Z |
| publishDate | 2008-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-eabfd986bd9b440f99e7fe7c7e26db692022-12-21T20:46:06ZengBMCMolecular Cancer1476-45982008-05-01713710.1186/1476-4598-7-37Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brainChiles Thomas CBlair DerekMarsh JeremyMulrooney Tiernan JMukherjee PurnaSeyfried Thomas N<p>Abstract</p> <p>Background</p> <p>AMP-activated protein kinase (AMPK) is a known physiological cellular energy sensor and becomes phosphorylated at Thr-172 in response to changes in cellular ATP levels. Activated AMPK acts as either an inducer or suppressor of apoptosis depending on the severity of energy stress and the presence or absence of certain functional tumor suppressor genes.</p> <p>Results</p> <p>Here we show that energy stress differentially affects AMPK phosphorylation and cell-death in brain tumor tissue and in tissue from contra-lateral normal brain. We compared TSC2 deficient CT-2A mouse astrocytoma cells with syngeneic normal astrocytes that were grown under identical condition <it>in vitro</it>. Energy stress induced by glucose withdrawal or addition of 2-deoxyglucose caused more ATP depletion, AMPK phosphorylation and apoptosis in CT-2A cells than in the normal astrocytes. Under normal energy conditions pharmacological stimulation of AMPK caused apoptosis in CT-2A cells but not in astrocytes. TSC2 siRNA treated astrocytes are hypersensitive to apoptosis induced by energy stress compared to control cells. AMPK phosphorylation and apoptosis were also greater in the CT-2A tumor tissue than in the normal brain tissue following implementation of dietary energy restriction. Inefficient mTOR and TSC2 signaling, downstream of AMPK, is responsible for CT-2A cell-death, while functional LKB1 may protect normal brain cells under energy stress.</p> <p>Conclusion</p> <p>Together these data demonstrates that AMPK phosphorylation induces apoptosis in mouse astrocytoma but may protect normal brain cells from apoptosis under similar energy stress condition. Therefore, using activator of AMPK along with glycolysis inhibitor could be a potential therapeutic approach for TSC2 deficient human malignant astrocytoma.</p>http://www.molecular-cancer.com/content/7/1/37 |
| spellingShingle | Chiles Thomas C Blair Derek Marsh Jeremy Mulrooney Tiernan J Mukherjee Purna Seyfried Thomas N Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain Molecular Cancer |
| title | Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain |
| title_full | Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain |
| title_fullStr | Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain |
| title_full_unstemmed | Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain |
| title_short | Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain |
| title_sort | differential effects of energy stress on ampk phosphorylation and apoptosis in experimental brain tumor and normal brain |
| url | http://www.molecular-cancer.com/content/7/1/37 |
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