Inorganic phosphate inhibits growth of human osteosarcoma U2OS cells via adenylate cyclase/cAMP pathway.
In order to elucidate how phosphate regulates cellular functions, we investigated the effects of inorganic phosphate (Pi) on adenylate cyclase (AC)/cyclic AMP (cAMP) axis. Here we describe that Pi treatment of human osteosarcoma U2OS cells results in a decrease of both intracellular cAMP levels and AC activity, and in a cell growth inhibition. The phosphate-triggered effects observed in U2OS cells are not a widespread phenomenon regarding all cell lines, since other cell lines screened respond differently to parallel Pi treatments. In U2OS cell line, the AC activity/cAMP downregulation is accompanied by significant variations in the levels of some membrane proteins belonging to the AC system. Remarkably, the above effects are blunted by pharmacological inhibition of sodium-dependent phosphate transport. Moreover, 8-Br-cAMP and other cAMP-elevating agents, such as IBMX and forskolin, interestingly, prevent the cell growth inhibition in response to phosphate. Our results enforce the increasing evidences of phosphate as a signaling molecule, identifying in U2OS cell line the AC/cAMP axis, as a novel-signaling pathway modulated by phosphate to ultimately affect cell growth.
Naviglio
Silvio
S
Department of Biochemistry and Biophysics, Second University of Naples, Medical School, 80138 Naples, Italy. silvio.naviglio@unina2.it
Spina
Annamaria
A
Chiosi
Emilio
E
Fusco
Anna
A
Illiano
Fausto
F
Pagano
Mario
M
Romano
Maria
M
Senatore
Giovanna
G
Sorrentino
Annunziata
A
Sorvillo
Luca
L
Illiano
Gennaro
G
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D012516:Osteosarcoma / Q000378:metabolism*; D010710:Phosphates / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors
D010710:Phosphates; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases