Activating stress-activated protein kinase-mediated cell death and inhibiting epidermal growth factor receptor signaling: a promising therapeutic strategy for prostate cancer.
Epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling, such as the Raf, mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 cascades. EGFR activation has been implicated in the transition of prostate cancer from androgen dependence to independence. Therefore, inhibition of EGFR may effectively suppress prostate cancer growth and progression. The goal of this study was to determine whether the natural compound psoralidin alters EGFR-mediated signaling resulting in the inhibition of prostate cancer growth. Results suggest that inhibition of EGFR alone (by serum deprivation) fails to induce stress-mediated protein kinases (SAPK), namely, Jun NH(2)-terminal kinase/c-Jun signaling, in androgen-independent prostate cancer (AIPC) cells. Treatment with psoralidin, however, inhibited both constitutive and EGF-induced EGFR activation and simultaneously triggered SAPK signaling, resulting in the induction of apoptosis in AIPC cells. In addition, psoralidin downregulated EGFR-regulated MAPK signaling and inhibited cell proliferation in AIPC cells. Oral administration of psoralidin effectively suppressed PC-3 xenograft tumors in nude mice. Compared with control tumors, inhibition of pEGFR expression and an increase in the phosphorylation, activation, and nuclear translocation of c-Jun were observed in psoralidin-treated tumor sections. Our studies suggest that psoralidin may be a potent therapeutic agent that modulates EGFR-mediated key epigenetic events in AIPC.
Kumar
Raj
R
Department of Clinical Sciences, College of Health Sciences, University of Kentucky, Lexington, Kentucky 40536-0200, USA.
Srinivasan
Sowmyalakshmi
S
Pahari
Pallab
P
Rohr
Jürgen
J
Damodaran
Chendil
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001572:Benzofurans / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003374:Coumarins / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014162:Transfection; D014183:Transplantation, Heterologous
D001572:Benzofurans; D003374:Coumarins; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; C102768:psoralidin