Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction
PTEN loss is considered a biomarker for activated phosphoinositide 3-kinase (PI3K)/AKT, a pathway frequently mutated in cancer, and was recently shown to confer resistance to dietary restriction. Here, we show that Pten loss is not sufficient to drive AKT activation and resistance to dietary restric...
| Main Authors: | , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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American Association for Cancer Research
2014
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| Online Access: | http://hdl.handle.net/1721.1/85099 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-7577-4612 https://orcid.org/0000-0002-1446-7256 |
| _version_ | 1810972694119710720 |
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| author | Curry, Natasha L. Mino-Kenudson, Mari Oliver, Trudy Yilmaz, Omer Yilmaz, Vedat O. Moon, Jade Y. Jacks, Tyler E. Sabatini, David M. Kalaany, Nada Y. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Curry, Natasha L. Mino-Kenudson, Mari Oliver, Trudy Yilmaz, Omer Yilmaz, Vedat O. Moon, Jade Y. Jacks, Tyler E. Sabatini, David M. Kalaany, Nada Y. |
| author_sort | Curry, Natasha L. |
| collection | MIT |
| description | PTEN loss is considered a biomarker for activated phosphoinositide 3-kinase (PI3K)/AKT, a pathway frequently mutated in cancer, and was recently shown to confer resistance to dietary restriction. Here, we show that Pten loss is not sufficient to drive AKT activation and resistance to dietary restriction in tumors with low growth factor receptor levels. We describe a murine Pten-null Kras-driven lung cancer model that harbors both dietary restriction–resistant, higher-grade, bronchiolar tumors with high AKT activity, and dietary restriction–sensitive, lower-grade, alveolar tumors with low AKT activity. We find that this phenotype is cell autonomous and that normal bronchiolar cells express higher levels of insulin-like growth factor-I receptor (IGF-IR) and of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), an endoplasmic reticulum enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF-IR levels and sensitize bronchiolar tumor cells to serum in vitro and to dietary restriction in vivo. Furthermore, we find that a significant percentage of human non–small cell lung carcinomas (NSCLC) have low AKT activity despite PTEN loss. SIGNIFICANCE: Our studies point to a heterogeneity of AKT activation in the same murine Pten-null lung tissue and in human NSCLC, further underscoring the challenges of personalizing cancer therapy based solely on cancer genotype. Our findings therefore indicate that the tumor response to anticancer therapies, including dietary restriction, needs to be based on PI3K/AKT activity per se, rather than on genetic alterations in the PTEN/PI3K pathway. |
| first_indexed | 2024-09-23T07:55:46Z |
| format | Article |
| id | mit-1721.1/85099 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T07:55:46Z |
| publishDate | 2014 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | mit-1721.1/850992022-09-30T01:03:40Z Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction Curry, Natasha L. Mino-Kenudson, Mari Oliver, Trudy Yilmaz, Omer Yilmaz, Vedat O. Moon, Jade Y. Jacks, Tyler E. Sabatini, David M. Kalaany, Nada Y. Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Yilmaz, Omer Jacks, Tyler E. Sabatini, David M. Oliver, Trudy PTEN loss is considered a biomarker for activated phosphoinositide 3-kinase (PI3K)/AKT, a pathway frequently mutated in cancer, and was recently shown to confer resistance to dietary restriction. Here, we show that Pten loss is not sufficient to drive AKT activation and resistance to dietary restriction in tumors with low growth factor receptor levels. We describe a murine Pten-null Kras-driven lung cancer model that harbors both dietary restriction–resistant, higher-grade, bronchiolar tumors with high AKT activity, and dietary restriction–sensitive, lower-grade, alveolar tumors with low AKT activity. We find that this phenotype is cell autonomous and that normal bronchiolar cells express higher levels of insulin-like growth factor-I receptor (IGF-IR) and of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), an endoplasmic reticulum enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF-IR levels and sensitize bronchiolar tumor cells to serum in vitro and to dietary restriction in vivo. Furthermore, we find that a significant percentage of human non–small cell lung carcinomas (NSCLC) have low AKT activity despite PTEN loss. SIGNIFICANCE: Our studies point to a heterogeneity of AKT activation in the same murine Pten-null lung tissue and in human NSCLC, further underscoring the challenges of personalizing cancer therapy based solely on cancer genotype. Our findings therefore indicate that the tumor response to anticancer therapies, including dietary restriction, needs to be based on PI3K/AKT activity per se, rather than on genetic alterations in the PTEN/PI3K pathway. Howard Hughes Medical Institute (Investigator) National Institutes of Health (U.S.) (NIH grant R01 AI047389) National Institutes of Health (U.S.) (NIH grant R01 CA129105) National Institutes of Health (U.S.) (NIH grant 2-P30-CA14051) Alexander and Margaret Stewart Trust (Award) Boston Children's Hospital David H. Koch Institute for Integrative Cancer Research at MIT (Anna Fuller Fund fellowship) 2014-02-26T18:36:09Z 2014-02-26T18:36:09Z 2013-05 Article http://purl.org/eprint/type/JournalArticle 2159-8274 2159-8290 http://hdl.handle.net/1721.1/85099 Curry, N. L., M. Mino-Kenudson, T. G. Oliver, O. H. Yilmaz, V. O. Yilmaz, J. Y. Moon, T. Jacks, D. M. Sabatini, and N. Y. Kalaany. “Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction.” Cancer Discovery 3, no. 8 (August 7, 2013): 908-921. https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-7577-4612 https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1158/2159-8290.cd-12-0507 Cancer Discovery Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research PMC |
| spellingShingle | Curry, Natasha L. Mino-Kenudson, Mari Oliver, Trudy Yilmaz, Omer Yilmaz, Vedat O. Moon, Jade Y. Jacks, Tyler E. Sabatini, David M. Kalaany, Nada Y. Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction |
| title | Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction |
| title_full | Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction |
| title_fullStr | Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction |
| title_full_unstemmed | Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction |
| title_short | Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction |
| title_sort | pten null tumors cohabiting the same lung display differential akt activation and sensitivity to dietary restriction |
| url | http://hdl.handle.net/1721.1/85099 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-7577-4612 https://orcid.org/0000-0002-1446-7256 |
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