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Lycopene inhibition of IGF-induced cancer cell growth depends on the level of cyclin D1


BACKGROUND: Insulin-like growth factors (IGFs) play an important role in normal and cancerous cell proliferation. Moreover, in recent studies IGF-I has been implicated as a major cancer risk factor. The tomato carotenoid lycopene and all-trans retinoic acid (atRA) have been shown to inhibit growth factor-induced proliferation of different types of cancer cells. This action is associated with inhibition of cell cycle progression in G0/G1 phase. Cyclin D1 acts as a growth factor sensor in G1 phase and is overexpressed in many breast cancer tumors. We have previously demonstrated that slowdown of serum-stimulated cell cycle progression from G1 to S phase by lycopene correlates with reduction in cyclin D1 levels, suggesting that the expression of this protein is a main target for lycopene's action. AIM OF THE STUDY: To determine whether the reported reduction in cyclin D1 level is the key mechanism for lycopene and atRA inhibitory action on IGF-I-induced cell cycle progression. RESULTS: Human breast (MCF-7) and endometrial (ECC-1) cancer cells were synchronized in G0/G1 phase by serum deprivation followed by stimulation with IGF-I. Cell treatment with lycopene and atRA inhibited IGF-I-stimulated cell cycle progression from G1 to S phase and decreased retinoblastoma protein (pRb) phosphorylation. These events were associated with a reduction in cyclin D1 and p21(CIP1/WAF1) level, but not that of p27(KIP1). To test the hypothesis that the decrease in cyclin D1 has a major role in the inhibitory effects of lycopene and atRA, we examined the ability of these two agents to suppress cell cycle progression in MCF-7.7D1.13 cells which are capable of expressing cyclin D1 under the control of the Zn-inducible metallothionein promoter. Our results showed that ectopic expression of cyclin D1 can overcome cell cycle inhibition caused by lycopene and atRA. CONCLUSIONS: Our findings suggest that attenuation of cyclin Dl levels by lycopene and atRA is an important mechanism for the reduction of the mitogenic action of IGF-I.

Type Journal
ISBN 1436-6207 (Print)
Authors Nahum, A.;Zeller, L.;Danilenko, M.;Prall, O. W.;Watts, C. K.;Sutherland, R. L.;Levy, J.;Sharoni, Y. :
Published Date 2006-01-01
Published Volume 45
Published Issue 5
Published Pages 275-82
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version