Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling - PubMed (original) (raw)

. 2009 Aug;29(8):3185-90.

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Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling

Sara M Johnson et al. Anticancer Res. 2009 Aug.

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Abstract

Background: Curcumin, a natural polyphenol product of the plant Curcuma longa, has been shown to inhibit the growth and progression of colorectal cancer; however, the anticancer mechanism of curcumin remains to be elucidated.

Materials and methods: Colorectal cancer cells were treated with curcumin and changes in proliferation, protein and mRNA levels were analyzed.

Results: Curcumin inhibited proliferation of colorectal cancer cells. This effect was mediated by inhibition of mammalian target of rapamycin (mTOR) signaling as evidenced by decreased phosphorylation of downstream effectors of mTOR complex 1 (mTORC1), p70S6K and 4E-BP1. Curcumin decreased total expression of mTOR, Raptor and Rictor protein and mRNA levels. Surprisingly, curcumin induced phosphorylation of Akt(Ser 473); this effect may be attributed to a decrease in levels of the PHLPP1 phosphatase, an inhibitor of Akt.

Conclusion: Our data suggest that curcumin, a natural compound, may exert its antiproliferative effects by inhibition of mTOR signaling and thus may represent a novel class of mTOR inhibitor.

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Figures

Figure 1

Figure 1. Curcumin inhibits colorectal cancer cell proliferation

HCT116 and KM20 CRC cells were treated with 0-100 μM curcumin for different time periods. A, Cell proliferation as assessed by crystal violet proliferation assay. B, Neutral red-based cytotoxicity assays were performed (*p<0.05 compared to the control).

Figure 2

Figure 2. Curcumin inhibits EGF-stimulated PI3K-Akt-mTOR signaling

HCT116 cells were serum starved overnight and treated with 25 μM curcumin for 2 hours, followed by stimulation with 20 ng/ml EGF for 45 minutes, prior to cell lysis. Western blotting was performed for rictor, raptor, and the phosphorylated and total forms of mTOR, p70S6K (Thr389), Akt (Ser473) and 4E-BP1 (Thr37/46), with β-Actin serving as a loading control.

Figure 3

Figure 3. Curcumin reduces mTOR, Raptor and Rictor mRNA levels in a dose-dependent fashion

HCT116 cells were treated with curcumin at the indicated doses for 6 hours. RNA was extracted for analysis using quantitative RT-PCR. Messenger RNA levels of mTOR, Raptor and Rictor after curcumin treatment are shown after normalization to 18S mRNA levels (*p<0.05 compared to the control).

Figure 4

Figure 4. Curcumin reduces mTOR, Raptor and Rictor protein expression in a dose-dependent fashion

HCT116 cells were treated with curcumin at the indicated doses for 6 hours and cells were lysed. Proteins were analyzed by western blotting. A, Representative Western blots of mTOR components and downstream signals. B, Densitometry graphs showing relative changes in protein expression normalized to β-actin.

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