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.