Activating stress-activated protein kinase-mediated cell death and inhibiting epidermal growth factor receptor signaling: a promising therapeutic strategy for prostate cancer.

Abstract

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.

• Authors: Raj Kumar, Sowmyalakshmi Srinivasan, Pallab Pahari, Jürgen Rohr, Chendil Damodaran
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 9 Pg. 2488-96 (Sep 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 20736346 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzofurans
• Coumarins
• ErbB Receptors
• JNK Mitogen-Activated Protein Kinases
• psoralidin

Topics

• Animals
• Apoptosis (drug effects, genetics)
• Benzofurans (therapeutic use)
• Cell Line, Tumor
• Coumarins (therapeutic use)
• Down-Regulation (drug effects)
• Enzyme Activation (drug effects)
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Humans
• Immunohistochemistry
• JNK Mitogen-Activated Protein Kinases (metabolism)
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Phosphorylation
• Prostatic Neoplasms (drug therapy, enzymology, genetics, pathology)
• Transfection
• Transplantation, Heterologous