Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

Quercetin inhibits HGF/c-Met signaling and HGF-stimulated melanoma cell migration and invasion

Authors: Hui-Hui Cao, Chi-Yan Cheng, Tao Su, Xiu-Qiong Fu, Hui Guo, Ting Li, Anfernee Kai-Wing Tse, Hiu-Yee Kwan, Hua Yu, Zhi-Ling Yu

Published in: Molecular Cancer | Issue 1/2015

Login to get access

Abstract

Background

Melanoma is notorious for its propensity to metastasize, which makes treatment extremely difficult. Receptor tyrosine kinase c-Met is activated in human melanoma and is involved in melanoma progression and metastasis. Hepatocyte growth factor (HGF)-mediated activation of c-Met signaling has been suggested as a therapeutic target for melanoma metastasis. Quercetin is a dietary flavonoid that exerts anti-metastatic effect in various types of cancer including melanoma. In a previous report, we demonstrated that quercetin inhibited melanoma cell migration and invasion in vitro, and prevented melanoma cell lung metastasis in vivo. In this study, we sought to determine the involvement of HGF/c-Met signaling in the anti-metastatic action of quercetin in melanoma.

Methods

Transwell chamber assay was conducted to determine the cell migratory and invasive abilities. Western blotting was performed to determine the expression levels and activities of c-Met and its downstream molecules. And immunoblotting was performed in BS3 cross-linked cells to examine the homo-dimerization of c-Met. Quantitative real-time PCR analysis was carried out to evaluate the mRNA expression level of HGF. Transient transfection was used to overexpress PAK or FAK in cell models. Student’s t-test was used in analyzing differences between two groups.

Results

Quercetin dose-dependently suppressed HGF-stimulated melanoma cell migration and invasion. Further study indicated that quercetin inhibited c-Met phosphorylation, reduced c-Met homo-dimerization and decreased c-Met protein expression. The effect of quercetin on c-Met expression was associated with a reduced expression of fatty acid synthase. In addition, quercetin suppressed the phosphorylation of c-Met downstream molecules including Gab1 (GRB2-associated-binding protein 1), FAK (Focal Adhesion Kinase) and PAK (p21-activated kinases). More importantly, overexpression of FAK or PAK significantly reduced the inhibitory effect of quercetin on the migration of the melanoma cells.

Conclusions

Our findings suggest that suppression of the HGF/c-Met signaling pathway contributes to the anti-metastatic action of quercetin in melanoma.
Appendix
Available only for authorised users
Literature
1.
Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220–41.CrossRefPubMed
2.
Cummins DL, Cummins JM, Pantle H, Silverman MA, Leonard AL, Chanmugam A. Cutaneous malignant melanoma. Mayo Clin Proc. 2006;81:500–7.CrossRefPubMed
3.
Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res. 2000;19:21–34.PubMed
4.
Alwan LM, Grossmann K, Sageser D, Van Atta J, Agarwal N, Gilreath JA. Comparison of acute toxicity and mortality after two different dosing regimens of high-dose interleukin-2 for patients with metastatic melanoma. Target Oncol. 2014;9:63–71.CrossRefPubMed
5.
Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105–16.PubMed
6.
Tam NN, Chung SS, Lee DT, Wong YC. Aberrant expression of hepatocyte growth factor and its receptor, c-Met, during sex hormone-induced prostatic carcinogenesis in the Noble rat. Carcinogenesis. 2000;21:2183–91.CrossRefPubMed
7.
Tolbert WD, Daugherty-Holtrop J, Gherardi E, Vande Woude G, Xu HE. Structural basis for agonism and antagonism of hepatocyte growth factor. Proc Natl Acad Sci U S A. 2010;107:13264–9.CrossRefPubMedCentralPubMed
8.
9.
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915–25.CrossRefPubMed
10.
Webb CP, Taylor GA, Jeffers M, Fiscella M, Oskarsson M, Resau JH, et al. Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/metastasis. Oncogene. 1998;17:2019–25.CrossRefPubMed
11.
12.
Chattopadhyay C, Ellerhorst JA, Ekmekcioglu S, Greene VR, Davies MA, Grimm EA. Association of activated c-Met with NRAS-mutated human melanomas. Int J Cancer. 2012;131:E56–65.CrossRefPubMedCentralPubMed
13.
Natali PG, Nicotra MR, Di Renzo MF, Prat M, Bigotti A, Cavaliere R, et al. Expression of the c-Met/HGF receptor in human melanocytic neoplasms: demonstration of the relationship to malignant melanoma tumour progression. Br J Cancer. 1993;68:746–50.CrossRefPubMedCentralPubMed
14.
Puri N, Ahmed S, Janamanchi V, Tretiakova M, Zumba O, Krausz T, et al. c-Met is a potentially new therapeutic target for treatment of human melanoma. Clin Cancer Res. 2007;13:2246–53.CrossRefPubMed
15.
Yu Y, Merlino G. Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis in a transgenic transplantation model. Cancer Res. 2002;62:2951–6.PubMed
16.
Otsuka T, Takayama H, Sharp R, Celli G, LaRochelle WJ, Bottaro DP, et al. c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype. Cancer Res. 1998;58:5157–67.PubMed
17.
Kenessey I, Keszthelyi M, Kramer Z, Berta J, Adam A, Dobos J, et al. Inhibition of c-Met with the specific small molecule tyrosine kinase inhibitor SU11274 decreases growth and metastasis formation of experimental human melanoma. Curr Cancer Drug Targets. 2010;10:332–42.CrossRefPubMed
18.
Surriga O, Rajasekhar VK, Ambrosini G, Dogan Y, Huang R, Schwartz GK. Crizotinib, a c-Met inhibitor, prevents metastasis in a metastatic uveal melanoma model. Mol Cancer Ther. 2013;12:2817–26.CrossRefPubMed
19.
Okamoto T. Safety of quercetin for clinical application (Review). Int J Mol Med. 2005;16:275–8.PubMed
20.
Gugler R, Leschik M, Dengler HJ. Disposition of quercetin in man after single oral and intravenous doses. Eur J Clin Pharmacol. 1975;9:229–34.CrossRefPubMed
21.
Russo M, Spagnuolo C, Tedesco I, Bilotto S, Russo GL. The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem Pharmacol. 2012;83:6–15.CrossRefPubMed
22.
Piantelli M, Maggiano N, Ricci R, Larocca LM, Capelli A, Scambia G, et al. Tamoxifen and quercetin interact with type II estrogen binding sites and inhibit the growth of human melanoma cells. J Invest Dermatol. 1995;105:248–53.CrossRefPubMed
23.
Loizzo MR, Said A, Tundis R, Hawas UW, Rashed K, Menichini F, et al. Antioxidant and antiproliferative activity of Diospyros lotus L. extract and isolated compounds. Plant Foods Hum Nutr. 2009;64:264–70.CrossRefPubMed
24.
Rosner K, Ropke C, Pless V, Skovgaard GL. Late type apoptosis and apoptosis free lethal effect of quercetin in human melanoma. Biosci Biotechnol Biochem. 2006;70:2169–77.CrossRefPubMed
25.
Caltagirone S, Rossi C, Poggi A, Ranelletti FO, Natali PG, Brunetti M, et al. Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer. 2000;87:595–600.CrossRefPubMed
26.
Piantelli M, Rossi C, Iezzi M, La Sorda R, Iacobelli S, Alberti S, et al. Flavonoids inhibit melanoma lung metastasis by impairing tumor cells endothelium interactions. J Cell Physiol. 2006;207:23–9.CrossRefPubMed
27.
Labbe D, Provencal M, Lamy S, Boivin D, Gingras D, Beliveau R. The flavonols quercetin, kaempferol, and myricetin inhibit hepatocyte growth factor-induced medulloblastoma cell migration. J Nutr. 2009;139:646–52.CrossRefPubMed
28.
Lee WJ, Wu LF, Chen WK, Wang CJ, Tseng TH. Inhibitory effect of luteolin on hepatocyte growth factor/scatter factor-induced HepG2 cell invasion involving both MAPK/ERKs and PI3K-Akt pathways. Chem Biol Interact. 2006;160:123–33.CrossRefPubMed
29.
Cao HH, Tse AK, Kwan HY, Yu H, Cheng CY, Su T, et al. Quercetin exerts anti-melanoma activities and inhibits STAT3 signaling. Biochem Pharmacol. 2014;87:424–34.CrossRefPubMed
30.
Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M. Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene. 2001;20:8125–35.CrossRefPubMed
31.
Coleman DT, Bigelow R, Cardelli JA. Inhibition of fatty acid synthase by luteolin post-transcriptionally down-regulates c-Met expression independent of proteosomal/lysosomal degradation. Mol Cancer Ther. 2009;8:214–24.CrossRefPubMedCentralPubMed
32.
Kapur P, Rakheja D, Roy LC, Hoang MP. Fatty acid synthase expression in cutaneous melanocytic neoplasms. Mod Pathol. 2005;18:1107–12.CrossRefPubMed
33.
de Andrade BA, Leon JE, Carlos R, Delgado-Azanero W, Mosqueda-Taylor A, Graner E, et al. Expression of fatty acid synthase (FASN) in oral nevi and melanoma. Oral Dis. 2011;17:808–12.CrossRefPubMed
34.
Innocenzi D, Alo PL, Balzani A, Sebastiani V, Silipo V, La Torre G, et al. Fatty acid synthase expression in melanoma. J Cutan Pathol. 2003;30:23–8.CrossRefPubMed
35.
Brusselmans K, Vrolix R, Verhoeven G, Swinnen JV. Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity. J Biol Chem. 2005;280:5636–45.CrossRefPubMed
36.
Daker M, Ahmad M, Khoo AS. Quercetin-induced inhibition and synergistic activity with cisplatin - a chemotherapeutic strategy for nasopharyngeal carcinoma cells. Cancer Cell Int. 2012;12:34.CrossRefPubMedCentralPubMed
37.
Gherardi E, Sharpe M, Lane K, Sirulnik A, Stoker M. Hepatocyte growth factor/scatter factor (HGF/SF), the c-met receptor and the behaviour of epithelial cells. Symp Soc Exp Biol. 1993;47:163–81.PubMed
38.
Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev. 2003;22:309–25.CrossRefPubMed
39.
Bigelow RL, Cardelli JA. The green tea catechins, (−)-Epigallocatechin-3-gallate (EGCG) and (−)-Epicatechin-3-gallate (ECG), inhibit HGF/Met signaling in immortalized and tumorigenic breast epithelial cells. Oncogene. 2006;25:1922–30.CrossRefPubMed
40.
Goydos JS, Mann B, Kim HJ, Gabriel EM, Alsina J, Germino FJ, et al. Detection of B-RAF and N-RAS mutations in human melanoma. J Am Coll Surg. 2005;200:362–70.CrossRefPubMed
41.
Uddin S, Hussain AR, Ahmed M, Bu R, Ahmed SO, Ajarim D, et al. Inhibition of fatty acid synthase suppresses c-Met receptor kinase and induces apoptosis in diffuse large B-cell lymphoma. Mol Cancer Ther. 2010;9:1244–55.CrossRefPubMed
42.
Hung CM, Kuo DH, Chou CH, Su YC, Ho CT, Way TD. Osthole suppresses hepatocyte growth factor (HGF)-induced epithelial-mesenchymal transition via repression of the c-Met/Akt/mTOR pathway in human breast cancer cells. J Agric Food Chem. 2011;59:9683–90.CrossRefPubMed
43.
Menendez JA, Vellon L, Mehmi I, Oza BP, Ropero S, Colomer R, et al. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc Natl Acad Sci U S A. 2004;101:10715–20.CrossRefPubMedCentralPubMed
44.
Swinnen JV, Van Veldhoven PP, Timmermans L, De Schrijver E, Brusselmans K, Vanderhoydonc F, et al. Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Biochem Biophys Res Commun. 2003;302:898–903.CrossRefPubMed
45.
Duhon D, Bigelow RL, Coleman DT, Steffan JJ, Yu C, Langston W, et al. The polyphenol epigallocatechin-3-gallate affects lipid rafts to block activation of the c-Met receptor in prostate cancer cells. Mol Carcinog. 2010;49:739–49.PubMed
46.
Lamson DW, Brignall MS. Antioxidants and cancer, part 3: quercetin. Altern Med Rev. 2000;5:196–208.PubMed
47.
Briaud I, Harmon JS, Kelpe CL, Segu VB, Poitout V. Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes. 2001;50:315–21.CrossRefPubMedCentralPubMed
48.
Wu YM, Liu CH, Huang MJ, Lai HS, Lee PH, Hu RH, et al. C1GALT1 enhances proliferation of hepatocellular carcinoma cells via modulating MET glycosylation and dimerization. Cancer Res. 2013;73:5580–90.CrossRefPubMed
49.
Sells MA, Knaus UG, Bagrodia S, Ambrose DM, Bokoch GM, Chernoff J. Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr Biol. 1997;7:202–10.CrossRefPubMed
50.
Metadata
Title
Quercetin inhibits HGF/c-Met signaling and HGF-stimulated melanoma cell migration and invasion
Authors
Hui-Hui Cao
Chi-Yan Cheng
Tao Su
Xiu-Qiong Fu
Hui Guo
Ting Li
Anfernee Kai-Wing Tse
Hiu-Yee Kwan
Hua Yu
Zhi-Ling Yu
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0367-4

Other articles of this Issue 1/2015

Molecular Cancer 1/2015 Go to the issue

Research

MicroRNA-31 controls G protein alpha-13 (GNA13) expression and cell invasion in breast cancer cells

Research

Identification of anti-tumour biologics using primary tumour models, 3-D phenotypic screening and image-based multi-parametric profiling

Research

Panobinostat reduces hypoxia-induced cisplatin resistance of non-small cell lung carcinoma cells via HIF-1α destabilization

Research

Cytoplasmic levels of cFLIP determine a broad susceptibility of breast cancer stem/progenitor-like cells to TRAIL

Short communication

The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis

Research

CRABP1 is associated with a poor prognosis in breast cancer: adding to the complexity of breast cancer cell response to retinoic acid
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits