RT Journal Article
SR Electronic
T1 Cannabinoid Receptor Activation Correlates with the Proapoptotic Action of the β<sub>2</sub>-Adrenergic Agonist (<em>R</em>,<em>R</em>′)-4-Methoxy-1-Naphthylfenoterol in HepG2 Hepatocarcinoma Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 157
OP 166
DO 10.1124/jpet.112.195206
VO 343
IS 1
A1 Paul, Rajib K.
A1 Ramamoorthy, Anuradha
A1 Scheers, Jade
A1 Wersto, Robert P.
A1 Toll, Lawrence
A1 Jimenez, Lucita
A1 Bernier, Michel
A1 Wainer, Irving W.
YR 2012
UL http://jpet.aspetjournals.org/content/343/1/157.abstract
AB Inhibition of cell proliferation by fenoterol and fenoterol derivatives in 1321N1 astrocytoma cells is consistent with β2-adrenergic receptor (β2-AR) stimulation. However, the events that result in fenoterol-mediated control of cell proliferation in other cell types are not clear. Here, we compare the effect of the β2-AR agonists (R,R′)-fenoterol (Fen) and (R,R′)-4-methoxy-1-naphthylfenoterol (MNF) on signaling and cell proliferation in HepG2 hepatocarcinoma cells by using Western blotting and [3H]thymidine incorporation assays. Despite the expression of β2-AR, no cAMP accumulation was observed when cells were stimulated with isoproterenol or Fen, although the treatment elicited both mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt activation. Unexpectedly, isoproterenol and Fen promoted HepG2 cell growth, but MNF reduced proliferation together with increased apoptosis. The mitogenic responses of Fen were attenuated by 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118,551), a β2-AR antagonist, whereas those of MNF were unaffected. Because of the coexpression of β2-AR and cannabinoid receptors (CBRs) and their impact on HepG2 cell proliferation, these Gαi/Gαo-linked receptors may be implicated in MNF signaling. Cell treatment with (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN 55,212-2), a synthetic agonist of CB1R and CB2R, led to growth inhibition, whereas inverse agonists of these receptors blocked MNF mitogenic responses without affecting Fen signaling. MNF responses were sensitive to pertussis toxin. The β2-AR-deficient U87MG cells were refractory to Fen, but responsive to the antiproliferative actions of MNF and WIN 55,212-2. The data indicate that the presence of the naphthyl moiety in MNF results in functional coupling to the CBR pathway, providing one of the first examples of a dually acting β2-AR-CBR ligand.