title: Oncogenic activation of the PI3K/Akt pathway promotes cellular glucose uptake by downregulating the expression of thioredoxin-interacting protein.
abstract: Oncogenic activation of the PI3K/Akt pathway is known to play an important role to promote glucose metabolism in cancer cells. However, the molecular mechanism through which the PI3K/Akt signalling pathway promotes glucose utilisation in cancer cells is still not well understood. It has recently been shown that the oncogenic activation of the PI3K/Akt/mTOR signalling in lung adenocarcinoma is important in promoting the localisation of glucose transporter 1 (GLUT1) at the plasma membrane. We thus hypothesised that the effect of constitutive activation of the PI3K/AKT signalling on glucose metabolism is mediated by thioredoxin interacting protein (TXNIP), a known regulator of the GLUT1 plasma membrane localisation. Consistent with previous studies, inhibition of the PI3K/Akt pathway decreased cellular glucose uptake. Furthermore, inhibition of PI3K/Akt signalling in non-small cell lung cancer (NSCLC) cell lines using clinically used tyrosine kinase inhibitors (TKIs) resulted in a decrease in GLUT1 membrane localisation. We also observed that inhibition of the PI3K/Akt pathway in various cell lines, including NSCLC cells, resulted in an increase in TXNIP expression. Importantly, knockdown of TXNIP using siRNA in the NSCLC cells promoted GLUT1 to be localised at the plasma membrane and reversed the effect of PI3K/Akt inhibitors. Together, our results suggest that the oncogenic activation of PI3K/Akt signalling promotes cellular glucose uptake, at least in part, through the regulation of TXNIP expression. This mechanism may contribute to the Warburg effect in cancer cells.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore.
authors.forename: Shin Yee
authors.initials: SY
authors.lastname: Hong
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Fa-Xing
authors.initials: FX
authors.lastname: Yu
authors.affiliation: School of Basic Medical Sciences, Zhejiang University College of Medicine, Zhejiang 310058, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore. Electronic address: bchth@nus.edu.sg.
authors.forename: Thilo
authors.initials: T
authors.lastname: Hagen
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D000077156:Gefitinib; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D015513:Oncogene Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002352:Carrier Proteins; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D005947:Glucose; D051272:Glucose Transporter Type 1; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; C486715:TXNIP protein, human
keywords: Cancer; GLUT1; Glucose; MondoA; PI3K/Akt pathway; TXNIP