title: Pten-null tumors cohabiting the same lung display differential AKT activation and sensitivity to dietary restriction.
abstract: 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.
authors.affiliation: Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston , MA 02115, USA.
authors.forename: Natasha L
authors.initials: NL
authors.lastname: Curry
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: Trudy G
authors.initials: TG
authors.lastname: Oliver
authors.forename: Omer H
authors.initials: OH
authors.lastname: Yilmaz
authors.forename: Vedat O
authors.initials: VO
authors.lastname: Yilmaz
authors.forename: Jade Y
authors.initials: JY
authors.lastname: Moon
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.forename: Nada Y
authors.initials: NY
authors.lastname: Kalaany
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011755:Pyrophosphatases / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D015513:Oncogene Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D011755:Pyrophosphatases; C485537:Pcph protein, mouse; C487757:Pten protein, mouse; C117634:ENTPD5 protein, human; C495971:Hras protein, mouse