Carcinogenesis Advance Access published online on November 19, 2005
Carcinogenesis, doi:10.1093/carcin/bgi272
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1 Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway NJ 08854, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway NJ 08854, USA
* To whom correspondence should be addressed. Many naturally occurring compounds, including
Received June 23, 2005
Revised October 26, 2005
Accepted November 12, 2005
CANCER BIOLOGY
Inhibition of EGFR signaling in human prostate cancer PC-3 cells by combination treatment with
Jung-Hwan Kim 1,
Changjiang Xu 1,
Young-Sam Keum 1,
Bandaru Reddy 2,
Allan Conney 2,
and
Ah-Ng Tony Kong 1 *
-phenylethyl isothiocyanate and curcumin
2 Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway NJ 08854, USA; Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway NJ 08854, USA
Ah-Ng Tony Kong, E-mail: Kongt{at}rci.rutgers.edu
Abstract 
-phenylethyl isothiocyanate (PEITC) and curcumin, exhibit significant anti-cancer chemopreventive effects. In this study, we investigated the combined effects of PEITC and curcumin in PC-3 human prostate cancer cells and in PC-3 cells that were stably transfected with an NF-
B luciferase plasmid (PC-3 C4). We found an additive effect of PEITC and curcumin for the induction of apoptosis. To elucidate the potential mechanisms of this effect, we studied several critical cellular signaling pathways, including the critical NF-B cell survival signal that is hyper-activated in PC-3 cells and many other cancers. PEITC and curcumin additively inhibited NF-B-luciferase activity. Furthermore, the combined treatment significantly increased the activity of poly (ADP-Ribose) polymerase (PARP) and cleavage of caspase-3 in correlation with apoptotic cell death. Studying upstream signaling events, we found that the phosphorylations of IB
and Akt (Ser473, Thr308) were significantly attenuated by the combination of PEITC and curcumin. As these events can be downstream of the activation of epidermal growth factor receptor (EGFR), we pretreated PC-3 cells with PEITC and curcumin and then stimulated them with EGF. EGFR phosphorylations (Y845 and Y1068) were dramatically suppressed by PEITC or curcumin, and more so by the combination. Importantly, the degree of Akt and PI3K phosphorylations induced by EGF were also significantly suppressed. We conclude that the simultaneous targeting of EGFR, Akt, and NF-B signaling pathways by PEITC and curcumin could be the molecular targets by which PEITC and curcumin exert their additive inhibitory effects on cell proliferation and ultimately lead to programmed cell death of tumor cells.B; Akt; cell death.
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