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Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis
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| Zeitschriftentitel: | Proceedings of the National Academy of Sciences |
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| Personen und Körperschaften: | , , , , , |
| In: | Proceedings of the National Academy of Sciences, 102, 2005, 1, S. 192-197 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Proceedings of the National Academy of Sciences
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| Schlagwörter: |
| author_facet |
Erdal, Hamdiye Berndtsson, Maria Castro, Juan Brunk, Ulf Shoshan, Maria C. Linder, Stig Erdal, Hamdiye Berndtsson, Maria Castro, Juan Brunk, Ulf Shoshan, Maria C. Linder, Stig |
|---|---|
| author |
Erdal, Hamdiye Berndtsson, Maria Castro, Juan Brunk, Ulf Shoshan, Maria C. Linder, Stig |
| spellingShingle |
Erdal, Hamdiye Berndtsson, Maria Castro, Juan Brunk, Ulf Shoshan, Maria C. Linder, Stig Proceedings of the National Academy of Sciences Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis Multidisciplinary |
| author_sort |
erdal, hamdiye |
| spelling |
Erdal, Hamdiye Berndtsson, Maria Castro, Juan Brunk, Ulf Shoshan, Maria C. Linder, Stig 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.0408592102 <jats:p>The p53 protein activates cellular death programs through multiple pathways. Because the high frequency of p53 mutations in human tumors is believed to contribute to resistance to commonly used chemotherapeutic agents, it is important to identify drugs that induce p53-independent cell death and to define the mechanisms of action of such drugs. Here we screened a drug library (the National Cancer Institute mechanistic set; 879 compounds with diverse mechanisms of actions) and identified 175 compounds that induced caspase cleavage of cytokeratin-18 in cultured HCT116 colon cancer cells at <5 μM. Interestingly, whereas most compounds elicited a stronger apoptotic response in cells with functional p53, significant apoptosis was observed also in p53-null cells. A subset of 15 compounds showing weak or no dependence on p53 for induction of apoptosis was examined in detail. Of these compounds, 11 were capable of activating caspase-3 in enucleated cells. Seven such compounds with nonnuclear targets were found to induce lysosomal membrane permeabilization (LMP). Translocation of the lysosomal proteases cathepsin B and cathepsin D into the cytosol was observed after treatment with these drugs, and apoptosis was inhibited by pepstatin A, an inhibitor of cathepsin D. Apoptosis depended on Bax, suggesting that LMP induced a mitochondrial apoptotic pathway. We conclude that a large number of potential anticancer drugs induce p53-independent apoptosis and that LMP is a mediator of many such responses.</jats:p> Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis Proceedings of the National Academy of Sciences |
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| title |
Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_unstemmed |
Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_full |
Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_fullStr |
Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_full_unstemmed |
Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_short |
Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_sort |
induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
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Multidisciplinary |
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http://dx.doi.org/10.1073/pnas.0408592102 |
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2005 |
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192-197 |
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<jats:p>The p53 protein activates cellular death programs through multiple pathways. Because the high frequency of p53 mutations in human tumors is believed to contribute to resistance to commonly used chemotherapeutic agents, it is important to identify drugs that induce p53-independent cell death and to define the mechanisms of action of such drugs. Here we screened a drug library (the National Cancer Institute mechanistic set; 879 compounds with diverse mechanisms of actions) and identified 175 compounds that induced caspase cleavage of cytokeratin-18 in cultured HCT116 colon cancer cells at <5 μM. Interestingly, whereas most compounds elicited a stronger apoptotic response in cells with functional p53, significant apoptosis was observed also in p53-null cells. A subset of 15 compounds showing weak or no dependence on p53 for induction of apoptosis was examined in detail. Of these compounds, 11 were capable of activating caspase-3 in enucleated cells. Seven such compounds with nonnuclear targets were found to induce lysosomal membrane permeabilization (LMP). Translocation of the lysosomal proteases cathepsin B and cathepsin D into the cytosol was observed after treatment with these drugs, and apoptosis was inhibited by pepstatin A, an inhibitor of cathepsin D. Apoptosis depended on Bax, suggesting that LMP induced a mitochondrial apoptotic pathway. We conclude that a large number of potential anticancer drugs induce p53-independent apoptosis and that LMP is a mediator of many such responses.</jats:p> |
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| author | Erdal, Hamdiye, Berndtsson, Maria, Castro, Juan, Brunk, Ulf, Shoshan, Maria C., Linder, Stig |
| author_facet | Erdal, Hamdiye, Berndtsson, Maria, Castro, Juan, Brunk, Ulf, Shoshan, Maria C., Linder, Stig, Erdal, Hamdiye, Berndtsson, Maria, Castro, Juan, Brunk, Ulf, Shoshan, Maria C., Linder, Stig |
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| description | <jats:p>The p53 protein activates cellular death programs through multiple pathways. Because the high frequency of p53 mutations in human tumors is believed to contribute to resistance to commonly used chemotherapeutic agents, it is important to identify drugs that induce p53-independent cell death and to define the mechanisms of action of such drugs. Here we screened a drug library (the National Cancer Institute mechanistic set; 879 compounds with diverse mechanisms of actions) and identified 175 compounds that induced caspase cleavage of cytokeratin-18 in cultured HCT116 colon cancer cells at <5 μM. Interestingly, whereas most compounds elicited a stronger apoptotic response in cells with functional p53, significant apoptosis was observed also in p53-null cells. A subset of 15 compounds showing weak or no dependence on p53 for induction of apoptosis was examined in detail. Of these compounds, 11 were capable of activating caspase-3 in enucleated cells. Seven such compounds with nonnuclear targets were found to induce lysosomal membrane permeabilization (LMP). Translocation of the lysosomal proteases cathepsin B and cathepsin D into the cytosol was observed after treatment with these drugs, and apoptosis was inhibited by pepstatin A, an inhibitor of cathepsin D. Apoptosis depended on Bax, suggesting that LMP induced a mitochondrial apoptotic pathway. We conclude that a large number of potential anticancer drugs induce p53-independent apoptosis and that LMP is a mediator of many such responses.</jats:p> |
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| spelling | Erdal, Hamdiye Berndtsson, Maria Castro, Juan Brunk, Ulf Shoshan, Maria C. Linder, Stig 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.0408592102 <jats:p>The p53 protein activates cellular death programs through multiple pathways. Because the high frequency of p53 mutations in human tumors is believed to contribute to resistance to commonly used chemotherapeutic agents, it is important to identify drugs that induce p53-independent cell death and to define the mechanisms of action of such drugs. Here we screened a drug library (the National Cancer Institute mechanistic set; 879 compounds with diverse mechanisms of actions) and identified 175 compounds that induced caspase cleavage of cytokeratin-18 in cultured HCT116 colon cancer cells at <5 μM. Interestingly, whereas most compounds elicited a stronger apoptotic response in cells with functional p53, significant apoptosis was observed also in p53-null cells. A subset of 15 compounds showing weak or no dependence on p53 for induction of apoptosis was examined in detail. Of these compounds, 11 were capable of activating caspase-3 in enucleated cells. Seven such compounds with nonnuclear targets were found to induce lysosomal membrane permeabilization (LMP). Translocation of the lysosomal proteases cathepsin B and cathepsin D into the cytosol was observed after treatment with these drugs, and apoptosis was inhibited by pepstatin A, an inhibitor of cathepsin D. Apoptosis depended on Bax, suggesting that LMP induced a mitochondrial apoptotic pathway. We conclude that a large number of potential anticancer drugs induce p53-independent apoptosis and that LMP is a mediator of many such responses.</jats:p> Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis Proceedings of the National Academy of Sciences |
| spellingShingle | Erdal, Hamdiye, Berndtsson, Maria, Castro, Juan, Brunk, Ulf, Shoshan, Maria C., Linder, Stig, Proceedings of the National Academy of Sciences, Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis, Multidisciplinary |
| title | Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_full | Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_fullStr | Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_full_unstemmed | Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_short | Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_sort | induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| title_unstemmed | Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis |
| topic | Multidisciplinary |
| url | http://dx.doi.org/10.1073/pnas.0408592102 |