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 1/2010

Open Access 01-12-2010 | Research

The chemopreventive retinoid 4HPR impairs prostate cancer cell migration and invasion by interfering with FAK/AKT/GSK3β pathway and β-catenin stability

Authors: Roberto Benelli, Stefano Monteghirfo, Roberta Venè, Francesca Tosetti, Nicoletta Ferrari

Published in: Molecular Cancer | Issue 1/2010

Login to get access

Abstract

Background

Prostate cancer shows an extremely slow progression, appearing in its metastatic, hormone refractory phenotype mostly in elderly men. The chemopreventive targeting of this tumor could accordingly delay its malignancy over life expectancy. The cancer chemopreventive retinoid N-(4 hydroxyphenyl)retinamide (4HPR) has already been shown to restrain prostate cancer growth in vitro and in vivo, though its mechanisms of action are only partially explained.

Results

We found that 4HPR impairs DU145 and PC3 prostate cancer cells migration and invasion by down-regulating FAK and AKT activation and by enhancing β-catenin degradation, causing the downregulation of target genes like cyclin D1, survivin and VEGF. This non-migratory phenotype was similarly produced in both cell lines by stable silencing of β-catenin. 4HPR was able to decrease AKT phosphorylation also when powerfully upregulated by IGF-1 and, consequently, to impair IGF-1-stimulated cell motility. Conversely, the expression of constitutively active AKT (myr-AKT) overcame the effects of 4HPR and β-catenin-silencing on cell migration. In addition, we found that BMP-2, a 4HPR target with antiangiogenic activity, decreased prostate cancer cell proliferation, migration and invasion by down-regulating the pathway described involving AKT phosphorylation, β-catenin stability and cyclin D1 expression.

Conclusion

These data point to 4HPR as a negative regulator of AKT phosphorylation, effectively targeting the β-catenin pathway and inducing a relatively benign phenotype in prostate cancer cells, limiting neoangiogenesis and cell invasion.
Appendix
Available only for authorised users
Literature
1.
Hail N Jr, Kim HJ, Lotan R: Mechanisms of fenretinide-induced apoptosis. Apoptosis. 2006, 11: 1677-1694. 10.1007/s10495-006-9289-3CrossRefPubMed
2.
Takahashi N, Watanabe Y, Maitani Y, Yamauchi T, Higashiyama K, Ohba T: p-Dodecylaminophenol derived from the synthetic retinoid, fenretinide: antitumor efficacy in vitro and in vivo against human prostate cancer and mechanism of action. Int J Cancer. 2008, 122: 689-698. 10.1002/ijc.23154CrossRefPubMed
3.
Shaker MR, Yang G, Timme TL, Park SH, Kadmon D, Ren C, Ji X, Lee HM, Sehgal I, Anzano M: Dietary 4-HPR suppresses the development of bone metastasis in vivo in a mouse model of prostate cancer progression. Clin Exp Metastasis. 2000, 18: 429-438. 10.1023/A:1010905309570CrossRefPubMed
4.
Pienta KJ, Nguyen NM, Lehr JE: Treatment of prostate cancer in the rat with the synthetic retinoid fenretinide. Cancer Res. 1993, 53: 224-226.PubMed
5.
Pollard M, Luckert PH, Sporn MB: Prevention of primary prostate cancer in Lobund-Wistar rats by N-(4-hydroxyphenyl)retinamide. Cancer Res. 1991, 51: 3610-3611.PubMed
6.
Slawin K, Kadmon D, Park SH, Scardino PT, Anzano M, Sporn MB, Thompson TC: Dietary fenretinide, a synthetic retinoid, decreases the tumor incidence and the tumor mass of ras+myc-induced carcinomas in the mouse prostate reconstitution model system. Cancer Res. 1993, 53: 4461-4465.PubMed
7.
Hsieh TC, Ng C, Wu JM: The synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) exerts antiproliferative and apoptosis-inducing effects in the androgen-independent human prostatic JCA-1 cells. Biochem Mol Biol Int. 1995, 37: 499-506.PubMed
8.
Igawa M, Tanabe T, Chodak GW, Rukstalis DB: N-(4-hydroxyphenyl) retinamide induces cell cycle specific growth inhibition in PC3 cells. Prostate. 1994, 24: 299-305. 10.1002/pros.2990240605CrossRefPubMed
9.
Sun SY, Yue P, Lotan R: Induction of apoptosis by N-(4-hydroxyphenyl)retinamide and its association with reactive oxygen species, nuclear retinoic acid receptors, and apoptosis-related genes in human prostate carcinoma cells. Mol Pharmacol. 1999, 55: 403-410.PubMed
10.
Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M: Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998, 279: 563-566. 10.1126/science.279.5350.563CrossRefPubMed
11.
Stattin P, Bylund A, Rinaldi S, Biessy C, Dechaud H, Stenman UH, Egevad L, Riboli E, Hallmans G, Kaaks R: Plasma insulin-like growth factor-I, insulin-like growth factor-binding proteins, and prostate cancer risk: a prospective study. J Natl Cancer Inst. 2000, 92: 1910-1917. 10.1093/jnci/92.23.1910CrossRefPubMed
12.
Shishodia S, Gutierrez AM, Lotan R, Aggarwal BB: N-(4-hydroxyphenyl)retinamide inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of I(kappa)B(alpha) kinase and nuclear factor-kappaB-regulated gene products. Cancer Res. 2005, 65: 9555-9565. 10.1158/0008-5472.CAN-05-1585CrossRefPubMed
13.
Ferrari N, Morini M, Pfeffer U, Minghelli S, Noonan DM, Albini A: Inhibition of Kaposi's sarcoma in vivo by fenretinide. Clin Cancer Res. 2003, 9: 6020-6029.PubMed
14.
Ferrari N, Pfeffer U, Dell'Eva R, Ambrosini C, Noonan DM, Albini A: The transforming growth factor-beta family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl)retinamide. Clin Cancer Res. 2005, 11: 4610-4619. 10.1158/1078-0432.CCR-04-2210CrossRefPubMed
15.
Tosetti F, Vene R, Arena G, Morini M, Minghelli S, Noonan DM, Albini A: N-(4-hydroxyphenyl)retinamide inhibits retinoblastoma growth through reactive oxygen species-mediated cell death. Mol Pharmacol. 2003, 63: 565-573. 10.1124/mol.63.3.565CrossRefPubMed
16.
Ribatti D, Alessandri G, Baronio M, Raffaghello L, Cosimo E, Marimpietri D, Montaldo PG, De Falco G, Caruso A, Vacca A, Ponzoni M: Inhibition of neuroblastoma-induced angiogenesis by fenretinide. Int J Cancer. 2001, 94: 314-321. 10.1002/ijc.1441CrossRefPubMed
17.
Appierto V, Cavadini E, Pergolizzi R, Cleris L, Lotan R, Canevari S, Formelli F: b>Decrease in drug accumulation and in tumour aggressiveness marker expression in a fenretinide-induced resistant ovarian tumour cell line. Br J Cancer. 2001, 84: 1528-1534. 10.1054/bjoc.2001.1826PubMedCentralCrossRefPubMed
18.
Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM, McEwan RN: A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res. 1987, 47: 3239-3245.PubMed
19.
Sonoda Y, Watanabe S, Matsumoto Y, Aizu-Yokota E, Kasahara T: FAK is the upstream signal protein of the phosphatidylinositol 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis of a human glioblastoma cell line. J Biol Chem. 1999, 274: 10566-10570. 10.1074/jbc.274.15.10566CrossRefPubMed
20.
van Nimwegen MJ, van de Water B: Focal adhesion kinase: a potential target in cancer therapy. Biochem Pharmacol. 2007, 73: 597-609. 10.1016/j.bcp.2006.08.011CrossRefPubMed
21.
Shukla S, Maclennan GT, Hartman DJ, Fu P, Resnick MI, Gupta S: Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int J Cancer. 2007, 121: 1424-1432. 10.1002/ijc.22862CrossRefPubMed
22.
Fang J, Ding M, Yang L, Liu LZ, Jiang BH: PI3K/PTEN/AKT signaling regulates prostate tumor angiogenesis. Cell Signal. 2007, 19: 2487-2497. 10.1016/j.cellsig.2007.07.025PubMedCentralCrossRefPubMed
23.
Sachdev D, Yee D: Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther. 2007, 6: 1-12. 10.1158/1535-7163.MCT-06-0080CrossRefPubMed
24.
Chen G, Shukeir N, Potti A, Sircar K, Aprikian A, Goltzman D, Rabbani SA: Up-regulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer. 2004, 101: 1345-1356. 10.1002/cncr.20518CrossRefPubMed
25.
Takahashi-Yanaga F, Sasaguri T: GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy. Cell Signal. 2008, 20: 581-589. 10.1016/j.cellsig.2007.10.018CrossRefPubMed
26.
Ma H, Nguyen C, Lee KS, Kahn M: Differential roles for the coactivators CBP and p300 on TCF/beta-catenin-mediated survivin gene expression. Oncogene. 2005, 24: 3619-3631. 10.1038/sj.onc.1208433CrossRefPubMed
27.
Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H, Mills GB, Kobayashi R, Hunter T, Lu Z: Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem. 2007, 282: 11221-11229. 10.1074/jbc.M611871200PubMedCentralCrossRefPubMed
28.
Lu Z, Ghosh S, Wang Z, Hunter T: Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell. 2003, 4: 499-515. 10.1016/S1535-6108(03)00304-0CrossRefPubMed
29.
Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W, Donowitz M, Tsichlis PN, Larue L: The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 2003, 63: 2172-2178.PubMed
30.
He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH, Tian Q, Zeng X, He X, Wiedemann LM: BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet. 2004, 36: 1117-1121. 10.1038/ng1430CrossRefPubMed
31.
Haramis AP, Begthel H, van den Born M, van Es J, Jonkheer S, Offerhaus GJ, Clevers H: De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science. 2004, 303: 1684-1686. 10.1126/science.1093587CrossRefPubMed
32.
Buijs JT, Rentsch CA, van der Horst G, van Overveld PG, Wetterwald A, Schwaninger R, Henriquez NV, Ten Dijke P, Borovecki F, Markwalder R: BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am J Pathol. 2007, 171: 1047-1057. 10.2353/ajpath.2007.070168PubMedCentralCrossRefPubMed
33.
Shukla S, MacLennan GT, Flask CA, Fu P, Mishra A, Resnick MI, Gupta S: Blockade of beta-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice. Cancer Res. 2007, 67: 6925-6935. 10.1158/0008-5472.CAN-07-0717CrossRefPubMed
34.
Thaller C, Shalev M, Frolov A, Eichele G, Thompson TC, Williams RH, Dillioglugil O, Kadmon D: Fenretinide therapy in prostate cancer: effects on tissue and serum retinoid concentration. J Clin Oncol. 2000, 18: 3804-3808.PubMed
35.
Tremblay L, Hauck W, Aprikian AG, Begin LR, Chapdelaine A, Chevalier S: Focal adhesion kinase (pp125FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma. Int J Cancer. 1996, 68: 164-171. 10.1002/(SICI)1097-0215(19961009)68:2<169::AID-IJC4>3.0.CO;2-WCrossRefPubMed
36.
Rovin JD, Frierson HF, Ledinh W, Parsons JT, Adams RB: Expression of focal adhesion kinase in normal and pathologic human prostate tissues. Prostate. 2002, 53: 124-132. 10.1002/pros.10114CrossRefPubMed
37.
Shimada K, Nakamura M, Ishida E, Kishi M, Yonehara S, Konishi N: Contributions of mitogen-activated protein kinase and nuclear factor kappa B to N-(4-hydroxyphenyl)retinamide-induced apoptosis in prostate cancer cells. Mol Carcinog. 2002, 35: 127-137. 10.1002/mc.10084CrossRefPubMed
38.
Mitra SK, Mikolon D, Molina JE, Hsia DA, Hanson DA, Chi A, Lim ST, Bernard-Trifilo JA, Ilic D, Stupack DG: Intrinsic FAK activity and Y925 phosphorylation facilitate an angiogenic switch in tumors. Oncogene. 2006, 25: 5969-5984. 10.1038/sj.onc.1209588CrossRefPubMed
39.
Shah S, Hecht A, Pestell R, Byers SW: Trans-repression of beta-catenin activity by nuclear receptors. J Biol Chem. 2003, 278: 48137-48145. 10.1074/jbc.M307154200CrossRefPubMed
40.
Easwaran V, Pishvaian M, Salimuddin , Byers S: Cross-regulation of beta-catenin-LEF/TCF and retinoid signaling pathways. Curr Biol. 1999, 9: 1415-1418. 10.1016/S0960-9822(00)80088-3CrossRefPubMed
41.
Xiao JH, Ghosn C, Hinchman C, Forbes C, Wang J, Snider N, Cordrey A, Zhao Y, Chandraratna RA: Adenomatous polyposis coli (APC)-independent regulation of beta-catenin degradation via a retinoid X receptor-mediated pathway. J Biol Chem. 2003, 278: 29954-29962. 10.1074/jbc.M304761200CrossRefPubMed
42.
Katoh M: Regulation of WNT signaling molecules by retinoic acid during neuronal differentiation in NT2 cells: threshold model of WNT action (review). Int J Mol Med. 2002, 10: 683-687.PubMed
43.
Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC: Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know?. Endocr Rev. 2005, 26: 898-915. 10.1210/er.2003-0034CrossRefPubMed
44.
Golubkov V, Garcia A, Markland FS: Action of fenretinide (4-HPR) on ovarian cancer and endothelial cells. Anticancer Res. 2005, 25: 249-253.PubMed
45.
Pagnan G, Di Paolo D, Carosio R, Pastorino F, Marimpietri D, Brignole C, Pezzolo A, Loi M, Galietta LJ, Piccardi F: The combined therapeutic effects of bortezomib and fenretinide on neuroblastoma cells involve endoplasmic reticulum stress response. Clin Cancer Res. 2009, 15: 1199-1209. 10.1158/1078-0432.CCR-08-2477CrossRefPubMed
46.
Lai TH, Fong YC, Fu WM, Yang RS, Tang CH: Osteoblasts-derived BMP-2 enhances the motility of prostate cancer cells via activation of integrins. Prostate. 2008, 68: 1341-1353. 10.1002/pros.20799CrossRefPubMed
47.
Dai J, Hall CL, Escara-Wilke J, Mizokami A, Keller JM, Keller ET: Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent and independent mechanisms. Cancer Res. 2008, 68: 5785-5794. 10.1158/0008-5472.CAN-07-6541PubMedCentralCrossRefPubMed
48.
Feeley BT, Krenek L, Liu N, Hsu WK, Gamradt SC, Schwarz EM, Huard J, Lieberman JR: Overexpression of noggin inhibits BMP-mediated growth of osteolytic prostate cancer lesions. Bone. 2006, 38: 154-166. 10.1016/j.bone.2005.07.015CrossRefPubMed
49.
Qiu T, Grizzle WE, Oelschlager DK, Shen X, Cao X: Control of prostate cell growth: BMP antagonizes androgen mitogenic activity with incorporation of MAPK signals in Smad1. Embo J. 2007, 26: 346-357. 10.1038/sj.emboj.7601499PubMedCentralCrossRefPubMed
50.
Ide H, Yoshida T, Matsumoto N, Aoki K, Osada Y, Sugimura T, Terada M: Growth regulation of human prostate cancer cells by bone morphogenetic protein-2. Cancer Res. 1997, 57: 5022-5027.PubMed
51.
Tomari K, Kumagai T, Shimizu T, Takeda K: Bone morphogenetic protein-2 induces hypophosphorylation of Rb protein and repression of E2F in androgen-treated LNCaP human prostate cancer cells. Int J Mol Med. 2005, 15: 253-258.PubMed
Metadata
Title
The chemopreventive retinoid 4HPR impairs prostate cancer cell migration and invasion by interfering with FAK/AKT/GSK3β pathway and β-catenin stability
Authors
Roberto Benelli
Stefano Monteghirfo
Roberta Venè
Francesca Tosetti
Nicoletta Ferrari
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-142

Other articles of this Issue 1/2010

Molecular Cancer 1/2010 Go to the issue

Research

Prostate apoptosis response protein 4 sensitizes human colon cancer cells to chemotherapeutic 5-FU through mediation of an NFκB and microRNA network

Research

HTLV-I p30 inhibits multiple S phase entry checkpoints, decreases cyclin E-CDK2 interactions and delays cell cycle progression

Research

Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci

Research

Polycomb repressor complex 2 regulates HOXA9 and HOXA10, activating ID2 in NK/T-cell lines

Research

Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors

Research

Molecular assays for the detection of prostate tumor derived nucleic acids in peripheral blood
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