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Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation
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| Zeitschriftentitel: | Cancer Research |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , , , , |
| In: | Cancer Research, 77, 2017, 12, S. 3217-3230 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
|
| Schlagwörter: |
| author_facet |
Tech, Katherine Tikunov, Andrey P. Farooq, Hamza Morrissy, A. Sorana Meidinger, Jessica Fish, Taylor Green, Sarah C. Liu, Hedi Li, Yisu Mungall, Andrew J. Moore, Richard A. Ma, Yussanne Jones, Steven J.M. Marra, Marco A. Vander Heiden, Matthew G. Taylor, Michael D. Macdonald, Jeffrey M. Gershon, Timothy R. Tech, Katherine Tikunov, Andrey P. Farooq, Hamza Morrissy, A. Sorana Meidinger, Jessica Fish, Taylor Green, Sarah C. Liu, Hedi Li, Yisu Mungall, Andrew J. Moore, Richard A. Ma, Yussanne Jones, Steven J.M. Marra, Marco A. Vander Heiden, Matthew G. Taylor, Michael D. Macdonald, Jeffrey M. Gershon, Timothy R. |
|---|---|
| author |
Tech, Katherine Tikunov, Andrey P. Farooq, Hamza Morrissy, A. Sorana Meidinger, Jessica Fish, Taylor Green, Sarah C. Liu, Hedi Li, Yisu Mungall, Andrew J. Moore, Richard A. Ma, Yussanne Jones, Steven J.M. Marra, Marco A. Vander Heiden, Matthew G. Taylor, Michael D. Macdonald, Jeffrey M. Gershon, Timothy R. |
| spellingShingle |
Tech, Katherine Tikunov, Andrey P. Farooq, Hamza Morrissy, A. Sorana Meidinger, Jessica Fish, Taylor Green, Sarah C. Liu, Hedi Li, Yisu Mungall, Andrew J. Moore, Richard A. Ma, Yussanne Jones, Steven J.M. Marra, Marco A. Vander Heiden, Matthew G. Taylor, Michael D. Macdonald, Jeffrey M. Gershon, Timothy R. Cancer Research Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation Cancer Research Oncology |
| author_sort |
tech, katherine |
| spelling |
Tech, Katherine Tikunov, Andrey P. Farooq, Hamza Morrissy, A. Sorana Meidinger, Jessica Fish, Taylor Green, Sarah C. Liu, Hedi Li, Yisu Mungall, Andrew J. Moore, Richard A. Ma, Yussanne Jones, Steven J.M. Marra, Marco A. Vander Heiden, Matthew G. Taylor, Michael D. Macdonald, Jeffrey M. Gershon, Timothy R. 0008-5472 1538-7445 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/0008-5472.can-16-3304 <jats:title>Abstract</jats:title> <jats:p>Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM. Cancer Res; 77(12); 3217–30. ©2017 AACR.</jats:p> Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation Cancer Research |
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American Association for Cancer Research (AACR), 2017 |
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American Association for Cancer Research (AACR), 2017 |
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0008-5472 1538-7445 |
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| title |
Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| title_unstemmed |
Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| title_full |
Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| title_fullStr |
Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| title_full_unstemmed |
Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| title_short |
Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| title_sort |
pyruvate kinase inhibits proliferation during postnatal cerebellar neurogenesis and suppresses medulloblastoma formation |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/0008-5472.can-16-3304 |
| publishDate |
2017 |
| physical |
3217-3230 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM. Cancer Res; 77(12); 3217–30. ©2017 AACR.</jats:p> |
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| author | Tech, Katherine, Tikunov, Andrey P., Farooq, Hamza, Morrissy, A. Sorana, Meidinger, Jessica, Fish, Taylor, Green, Sarah C., Liu, Hedi, Li, Yisu, Mungall, Andrew J., Moore, Richard A., Ma, Yussanne, Jones, Steven J.M., Marra, Marco A., Vander Heiden, Matthew G., Taylor, Michael D., Macdonald, Jeffrey M., Gershon, Timothy R. |
| author_facet | Tech, Katherine, Tikunov, Andrey P., Farooq, Hamza, Morrissy, A. Sorana, Meidinger, Jessica, Fish, Taylor, Green, Sarah C., Liu, Hedi, Li, Yisu, Mungall, Andrew J., Moore, Richard A., Ma, Yussanne, Jones, Steven J.M., Marra, Marco A., Vander Heiden, Matthew G., Taylor, Michael D., Macdonald, Jeffrey M., Gershon, Timothy R., Tech, Katherine, Tikunov, Andrey P., Farooq, Hamza, Morrissy, A. Sorana, Meidinger, Jessica, Fish, Taylor, Green, Sarah C., Liu, Hedi, Li, Yisu, Mungall, Andrew J., Moore, Richard A., Ma, Yussanne, Jones, Steven J.M., Marra, Marco A., Vander Heiden, Matthew G., Taylor, Michael D., Macdonald, Jeffrey M., Gershon, Timothy R. |
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| description | <jats:title>Abstract</jats:title> <jats:p>Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM. Cancer Res; 77(12); 3217–30. ©2017 AACR.</jats:p> |
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| imprint_str_mv | American Association for Cancer Research (AACR), 2017 |
| institution | DE-D275, DE-Bn3, DE-Brt1, DE-D161, DE-Zwi2, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229 |
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| spelling | Tech, Katherine Tikunov, Andrey P. Farooq, Hamza Morrissy, A. Sorana Meidinger, Jessica Fish, Taylor Green, Sarah C. Liu, Hedi Li, Yisu Mungall, Andrew J. Moore, Richard A. Ma, Yussanne Jones, Steven J.M. Marra, Marco A. Vander Heiden, Matthew G. Taylor, Michael D. Macdonald, Jeffrey M. Gershon, Timothy R. 0008-5472 1538-7445 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/0008-5472.can-16-3304 <jats:title>Abstract</jats:title> <jats:p>Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM. Cancer Res; 77(12); 3217–30. ©2017 AACR.</jats:p> Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation Cancer Research |
| spellingShingle | Tech, Katherine, Tikunov, Andrey P., Farooq, Hamza, Morrissy, A. Sorana, Meidinger, Jessica, Fish, Taylor, Green, Sarah C., Liu, Hedi, Li, Yisu, Mungall, Andrew J., Moore, Richard A., Ma, Yussanne, Jones, Steven J.M., Marra, Marco A., Vander Heiden, Matthew G., Taylor, Michael D., Macdonald, Jeffrey M., Gershon, Timothy R., Cancer Research, Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation, Cancer Research, Oncology |
| title | Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| title_full | Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| title_fullStr | Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| title_full_unstemmed | Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| title_short | Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| title_sort | pyruvate kinase inhibits proliferation during postnatal cerebellar neurogenesis and suppresses medulloblastoma formation |
| title_unstemmed | Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/0008-5472.can-16-3304 |