Phospholipase D-mTOR requirement for the Warburg effect in human cancer cells.
A characteristic of cancer cells is the generation of lactate from glucose in spite of adequate oxygen for oxidative phosphorylation. This property - known as the "Warburg effect" or aerobic glycolysis - contrasts with anaerobic glycolysis, which is triggered in hypoxic normal cells. The Warburg effect is thought to provide a means for cancer cells to survive under conditions where oxygen is limited and to generate metabolites necessary for cell growth. The shift from oxidative phosphorylation to glycolysis in response to hypoxia is mediated by the production of hypoxia-inducible factor (HIF) - a transcription factor family that stimulates the expression of proteins involved in glucose uptake and glycolysis. We reported previously that elevated phospholipase D (PLD) activity in renal and breast cancer cells is required for the expression of the α subunits of HIF1 and HIF2. We report here that the aerobic glycolysis observed in human breast and renal cancer cells is dependent on the elevated PLD activity. Intriguingly, the effect of PLD on the Warburg phenotype was dependent on the mammalian target of rapamycin complex 1 (mTORC1) in the breast cancer cells and on mTORC2 in the renal cancer cells. These data indicate that elevated PLD-mTOR signaling, which is common in human cancer cells, is critical for the metabolic shift to aerobic glycolysis.
Toschi
Alfredo
A
Department of Biological Sciences, Hunter College of the City University of New York, NY 10021, USA.
Lee
Evan
E
Thompson
Sebastian
S
Gadir
Noga
N
Yellen
Paige
P
Drain
C Michael
CM
Ohh
Michael
M
Foster
David A
DA
D045744:Cell Line, Tumor; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000032:analysis; D006019:Glycolysis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011506:Proteins; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000502:physiology
C493245:CRTC2 protein, human; D051246:Glucose Transport Proteins, Facilitative; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D010739:Phospholipase D; D005947:Glucose
J Biol Chem. 1999 Jan 1;274(1):494-502
9867870
Neoplasia. 2006 Aug;8(8):623-9
16925945
Oncogene. 2003 Jun 19;22(25):3937-42
12813467
Mol Cell Biol. 2001 Jan;21(2):595-602
11134345
Biochim Biophys Acta. 2009 Sep;1791(9):949-55
19264150
Anticancer Agents Med Chem. 2008 Apr;8(3):305-12
18393789
Curr Opin Genet Dev. 2008 Feb;18(1):54-61
18387799
Expert Rev Anticancer Ther. 2004 Aug;4(4):691-701
15270672
EMBO J. 1997 Aug 1;16(15):4519-30
9303296
Mol Cell. 1998 Jun;1(7):959-68
9651579
Science. 2005 Feb 18;307(5712):1098-101
15718470
Mol Cell Biol. 2009 Mar;29(6):1411-20
19114562
PLoS Biol. 2003 Dec;1(3):E83
14691554
Oncogene. 2008 Jan 24;27(5):585-95
17684489
Oncogene. 2005 Jan 20;24(4):672-9
15580312
Cancer Cell. 2003 Nov;4(5):343-8
14667501
Cancer Res. 2004 Jun 1;64(11):3892-9
15172999
Cell Metab. 2008 Jan;7(1):11-20
18177721
Mol Cell Biol. 1998 Feb;18(2):732-41
9447969
Science. 2001 Nov 30;294(5548):1942-5
11729323
Mol Med. 2010 Mar;16(3-4):144-53
20062820
J Biol Chem. 2006 Jun 9;281(23):15862-8
16595654
Cancer Cell. 2007 Jul;12(1):9-22
17613433
Curr Opin Genet Dev. 2007 Feb;17(1):71-7
17208433
Science. 2009 May 22;324(5930):1029-33
19460998
Cell. 2001 Oct 5;107(1):43-54
11595184
Biochem Biophys Res Commun. 2002 Nov 8;298(4):474-7
12408976
Biochem Soc Trans. 2007 Apr;35(Pt 2):231-5
17371246
Oncogene. 2008 Apr 24;27(19):2746-53
17998935
Semin Oncol. 2006 Oct;33(5):588-95
17045088
Cancer Cell. 2006 Jun;9(6):419-20
16766260
Cell Oncol. 2006;28(5-6):327-9
17167185
Cell. 2007 Jun 29;129(7):1261-74
17604717
Curr Top Dev Biol. 2006;76:217-57
17118268
J Cell Sci. 2009 Oct 15;122(Pt 20):3589-94
19812304
Science. 1956 Aug 10;124(3215):269-70
13351639
Cancer Cell. 2008 Jun;13(6):472-82
18538731
Cell Metab. 2006 Mar;3(3):177-85
16517405
Cell. 2006 Feb 10;124(3):471-84
16469695
Science. 1956 Feb 24;123(3191):309-14
13298683
Cancer Cell. 2006 Jun;9(6):425-34
16766262