Magnolol induces apoptosis via inhibiting the EGFR/PI3K/Akt signaling pathway in human prostate cancer cells.
We observed that treatment of prostate cancer cells for 24 h with magnolol, a phenolic component extracted from the root and stem bark of the oriental herb Magnolia officinalis, induced apoptotic cell death in a dose- and time-dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in magnolol-treated cells. Treatment of PC-3 cells with an apoptosis-inducing concentration of magnolol (60 microM) resulted in a rapid decrease in the level of phosphorylated Akt leading to inhibition of its kinase activity. Magnolol treatment (60 microM) also caused a decrease in Ser((136)) phosphorylation of Bad (a proapoptotic protein), which is a downstream target of Akt. Protein interaction assay revealed that Bcl-xL, an anti-apoptotic protein, was associated with Bad during treatment with magnolol. We also observed that during treatment with magnolol, translocation of Bax to the mitochondrial membrane occurred and the translocation was accompanied by cytochrome c release, and cleavage of procaspase-8, -9, -3, and poly(ADP-ribose) polymerase (PARP). Similar results were observed in human colon cancer HCT116Bax(+/-) cell line, but not HCT116Bax(-/-) cell line. Interestingly, at similar concentrations (60 microM), magnolol treatment did not affect the viability of normal human prostate epithelial cell (PrEC) line. We also observed that apoptotic cell death by magnolol was associated with significant inhibition of pEGFR, pPI3K, and pAkt. These results suggest that one of the mechanisms of the apoptotic activity of magnolol involves its effect on epidermal growth factor receptor (EGFR)-mediated signaling transduction pathways.
Lee
Dae-Hee
DH
Department of Surgery and Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Szczepanski
Miroslaw-Jerzy
MJ
Lee
Yong J
YJ
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D045304:Cytochromes c; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D017705:Lignans; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C005498:magnolol