Nutr Res Pract.  2013 Dec;7(6):439-445.

Anticarcinogenic effect of quercetin by inhibition of insulin-like growth factor (IGF)-1 signaling in mouse skin cancer

• Jung M
• Bu SY
• Tak KH
• Park JE
• Kim E

Abstract

It has been shown that dysregulation of IGF-1 signaling is associated with tumor incidence and progression, whereas blockade of the signaling can effectively inhibit carcinogenesis. Although several mechanisms of anticancer activity of quercetin were proposed, molecular targets of quercetin have not been identified yet. Hence, we assessed the effect of quercetin on IGF-1 signaling inhibition in BK5.IGF-1 transgenic (Tg) mice, which over-expresses IGF-1 in the skin epidermis. A quercetin diet (0.02% wt/wt) for 20 weeks remarkably delayed the incidence of skin tumor by 2 weeks and reduced tumor multiplicity by 35% in a 7,12-dimethylbenz(a)anthracene (DMBA)-tetradecanoyl phorbol-13-acetate (TPA) two stage mouse skin carcinogenesis protocol. Moreover, skin hyperplasia in Tg mice was significantly inhibited by a quercetin supplementation. Further analysis of the MT1/2 skin papilloma cell line showed that a quercetin treatment dose dependently suppressed IGF-1 induced phosphorylation of the IGF-1 receptor (IGF-1R), insulin receptor substrate (IRS)-1, Akt and S6K; however, had no effect on the phosphorylation of PTEN. Additionally, the quercetin treatment inhibited IGF-1 stimulated cell proliferation in a dose dependent manner. Taken together, these data suggest that quercetin has a potent anticancer activity through the inhibition of IGF-1 signaling.

Keyword

Quercetin; IGF-1; carcinogenesis; mouse skin cancer

MeSH Terms

Animals
Anticarcinogenic Agents*
Cell Line
Cell Proliferation
Diet
Epidermis
Hyperplasia
Incidence
Insulin-Like Growth Factor I
Mice*
Papilloma
Phosphorylation
Quercetin*
Receptor, IGF Type 1
Receptor, Insulin
Skin Neoplasms*
Skin*
Anticarcinogenic Agents
Insulin-Like Growth Factor I
Quercetin
Receptor, IGF Type 1
Receptor, Insulin

Figure

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  Fig. 1 Body weight change. In experiment 1, BK5.IGF-1 Tg mice in the control (n = 8) and quercetin (n = 9) diet groups were initiated with 200 nmol (50 µg) of DMBA and promoted with 6.5 nmol (4 µg) of TPA in 200 µl of acetone twice a week for 20 weeks. The body weight of BK5.IGF-1 Tg mice was measured once a week during a 20-week experimental period. Values are the mean ± SE.

• 

  Fig. 2 Inhibition of skin tumor multiplicity by quercetin supplementation. A) Tumor incidence and B) tumor multiplicity of the control (n = 8) and quercetin (n = 9) diet groups were recorded weekly in experiment 1. C) Spontaneous tumor development was recorded. Three mice of the control group and one mouse in the quercetin group developed a total of 9 and 2 spontaneous tumors, respectively. D) Photographs of spontaneous tumor development in the non-TPA treated area in BK5.IGF-1 Tg mice. Values are the mean ± SE. *P < 0.05, **P < 0.01 and ***P < 0.001 when compared to the control group.

• 

  Fig. 3 Effect of quercetin on skin epidermal hyperplasia and basal cell proliferation. A) Histological analysis of acetone and TPA-treated BK5.IGF-1 Tg mouse skin. At the end of experiment 2, tissue sections were immunostained with an antibody against BrdU and photographed at 200X. The dorsal skins of BK5.IGF-1 Tg mice were fed with a) control diet treated with acetone, b) quercetin diet treated with acetone, c) control diet treated with TPA, and d) quercetin diet treated with TPA. B) Labeling index of acetone or TPA-treated mouse skin in each diet group. The index represents the percentage of the BrdU positive cells relative to the total number of the basal cells in the interfollicular epidermis. Each value is the mean ± SE of labeling indices from 3 mice/group. *P < 0.05

• 

  Fig. 4 Inhibition of IGF-1R activation and downstream effectors by quercetin in MT1/2 cells. A) Serum starved MT1/2 cells were treated with indicated doses (10 µM - 50 µM) of quercetin for 1 hr and then stimulated with IGF-1 (20 ng/ml) for 30 min. The phosphorylation and protein levels were determined by immunoblotting with the appropriate antibodies, as indicated. B) Cell viability was assessed by MTT assay. C) Cells were grown in serum free media and treated with IGF-1 (20 ng/ml) and indicated doses (10-50 µM) of quercetin for 48 hr. Proliferation of MT1/2 cells were measured by an MTT assay. Values are expressed as the means ± SE. Significant differences (P < 0.05) are indicated by different letters. SFM: serum free media, NS: not significant.

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