title: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling regulates mitochondrial biogenesis and respiration via estrogen-related receptor α (ERRα).
abstract: Mitochondrial abnormalities are associated with cancer development, yet how oncogenic signals affect mitochondrial functions has not been fully understood. In this study, we investigate the relationship between mitochondrial alterations and PI3K/protein kinase B (AKT) signaling activation using hepatocytes and liver tissues as our experimental models. We show here that liver-specific deletion of Pten, which leads to activation of PI3K/AKT, is associated with elevated oxidative stress, increased mitochondrial mass, and augmented respiration accompanied by enhanced glycolysis. Consistent with these observations, estrogen-related receptor α (ERRα), an orphan nuclear receptor known for its role in mitochondrial biogenesis, is up-regulated in the absence of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Our pharmacological and genetic studies show that PI3K/AKT activity regulates the expression of ERRα and mitochondrial biogenesis/respiration. Furthermore, cAMP-response element-binding protein, as a downstream target of AKT, plays a role in the regulation of ERRα, independent of PKA signaling. ERRα regulates reactive oxygen species production, and ERRα knockdown attenuates proliferation and colony-forming potential in Pten-null hepatocytes. Finally, analysis of clinical datasets from liver tissues showed a negative correlation between expressions of ERRα and PTEN in patients with liver cancer. Therefore, this study has established a previously unrecognized link between a growth signal and mitochondrial metabolism.
authors.affiliation: From Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: From Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089.
authors.forename: Lina
authors.initials: L
authors.lastname: He
authors.affiliation: From Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089.
authors.forename: Ni
authors.initials: N
authors.lastname: Zeng
authors.affiliation: Department of Dermatology, Norris Comprehensive Cancer Center, Keck Medical Center, University of Southern California, Los Angeles, California 90033, and.
authors.forename: Divya
authors.initials: D
authors.lastname: Sahu
authors.affiliation: From Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089,; Biochemistry, Keck School of Medicine, and.
authors.forename: Enrique
authors.initials: E
authors.lastname: Cadenas
authors.affiliation: Pharmaceutical Sciences, School of Pharmacy, University of Colorado, Aurora, Colorado 80045.
authors.forename: Colin
authors.initials: C
authors.lastname: Shearn
authors.affiliation: Department of Dermatology, Norris Comprehensive Cancer Center, Keck Medical Center, University of Southern California, Los Angeles, California 90033, and.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: From Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089,; the Departments of Pathology and. Electronic address: bstiles@usc.edu.
authors.forename: Bangyan L
authors.initials: BL
authors.lastname: Stiles
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C494929:PTEN protein, human; C487757:Pten protein, mouse
keywords: Akt PKB; CREB; Estrogen-related Receptor α (ERRα); Mitochondria; Mitochondrial Biogenesis; Mitochondrial Mass; Oxygen Consumption Rate (OCR); PGC-1; PI 3-Kinase (PI3K); PTEN