Skip to main content
Top
Published in: Pathology & Oncology Research 2/2020

01-04-2020 | Prostate Cancer | Original Article

Phloretin Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species

Authors: Ukjin Kim, C-Yoon Kim, Ji Min Lee, Hanseul Oh, Bokyeong Ryu, Jin Kim, Jae-Hak Park

Published in: Pathology & Oncology Research | Issue 2/2020

Login to get access

Abstract

Phloretin is a flavonoid with known anticancer activities. However, we do not fully understand how phloretin mitigates prostate cancer on the molecular level. In the present study, we examined changes in proliferation, colony formation, and migration after phloretin treatment in human prostate cancer cells PC3 and DU145. We measured reactive oxygen species (ROS) and gene expression. Phloretin increased ROS and suppressed cell proliferation, migration, and colony formation in both cell lines. Additionally, phloretin treatment increased oxidative stress, as demonstrated through lower antioxidant enzymes (catalase, SOD2, Gpx1, Gpx3). In addition, their regulator CISD2 decreased in expression. We also found that increased ROS significantly downregulated multiple components of the Wnt/β-catenin signaling pathway (β-catenin, TCF4, FoxA2, c-Myc) and Twist1. Thus, anticancer activity of phloretin against human prostate cancer cells occurs through generating ROS to influence Wnt/β-catenin signaling. The results of this study suggest that phloretin has a therapeutic effect on prostate cancer in vitro, inhibiting the proliferation and migration of cancer cell lines PC3 and DU145. The mechanism of phloretin appears to be increasing ROS production. We thus recommend phloretin as a promising anticancer therapeutic agent.
Literature
1.
go back to reference Kohler BA, Sherman RL, Howlader N, Jemal A, Ryerson AB, Henry KA, Boscoe FP, Cronin KA, Lake A, Noone A-M (2015) Annual report to the nation on the status of cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst 107(6):djv048PubMedPubMedCentral Kohler BA, Sherman RL, Howlader N, Jemal A, Ryerson AB, Henry KA, Boscoe FP, Cronin KA, Lake A, Noone A-M (2015) Annual report to the nation on the status of cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst 107(6):djv048PubMedPubMedCentral
2.
go back to reference Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, Bray F (2012) International variation in prostate cancer incidence and mortality rates. Eur Urol 61(6):1079–1092PubMed Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, Bray F (2012) International variation in prostate cancer incidence and mortality rates. Eur Urol 61(6):1079–1092PubMed
3.
go back to reference Khandrika L, Kumar B, Koul S, Maroni P, Koul HK (2009) Oxidative stress in prostate cancer. Cancer Lett 282(2):125–136PubMedPubMedCentral Khandrika L, Kumar B, Koul S, Maroni P, Koul HK (2009) Oxidative stress in prostate cancer. Cancer Lett 282(2):125–136PubMedPubMedCentral
4.
go back to reference Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11(2):85–95 Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11(2):85–95
5.
go back to reference Korswagen HC (2006) Regulation of the Wnt/β-catenin pathway by redox signaling. Dev Cell 10(6):687–688PubMed Korswagen HC (2006) Regulation of the Wnt/β-catenin pathway by redox signaling. Dev Cell 10(6):687–688PubMed
6.
go back to reference Yu X, Wang Y, Jiang M, Bierie B, Roy-Burman P, Shen MM, Taketo MM, Wills M, Matusik RJ (2009) Activation of β-catenin in mouse prostate causes HGPIN and continuous prostate growth after castration. Prostate 69(3):249–262PubMedPubMedCentral Yu X, Wang Y, Jiang M, Bierie B, Roy-Burman P, Shen MM, Taketo MM, Wills M, Matusik RJ (2009) Activation of β-catenin in mouse prostate causes HGPIN and continuous prostate growth after castration. Prostate 69(3):249–262PubMedPubMedCentral
7.
go back to reference Miller JR (2001) The wnts. Genome Biol 3(1):reviews3001. 3001 Miller JR (2001) The wnts. Genome Biol 3(1):reviews3001. 3001
8.
go back to reference Chesire DR, Ewing CM, Gage WR, Isaacs WB (2002) In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis. Oncogene 21(17):2679–2694PubMed Chesire DR, Ewing CM, Gage WR, Isaacs WB (2002) In vitro evidence for complex modes of nuclear β-catenin signaling during prostate growth and tumorigenesis. Oncogene 21(17):2679–2694PubMed
9.
go back to reference Shin SY, Kim CG, Jho E-H, Rho M-S, Kim YS, Kim Y-H, Lee YH (2004) Hydrogen peroxide negatively modulates Wnt signaling through downregulation of β-catenin. Cancer Lett 212(2):225–231PubMed Shin SY, Kim CG, Jho E-H, Rho M-S, Kim YS, Kim Y-H, Lee YH (2004) Hydrogen peroxide negatively modulates Wnt signaling through downregulation of β-catenin. Cancer Lett 212(2):225–231PubMed
11.
go back to reference Devi MA, Das N (1993) In vitro effects of natural plant polyphenols on the proliferation of normal and abnormal human lymphocytes and their secretions of interleukin-2. Cancer Lett 69(3):191–196PubMed Devi MA, Das N (1993) In vitro effects of natural plant polyphenols on the proliferation of normal and abnormal human lymphocytes and their secretions of interleukin-2. Cancer Lett 69(3):191–196PubMed
12.
go back to reference Zhu S-P, Liu G, Wu X-T, Chen F-X, Liu J-Q, Zhou Z-H, Zhang J-F, Fei S-J (2013) The effect of phloretin on human γδ T cells killing colon cancer SW-1116 cells. Int Immunopharmacol 15(1):6–14PubMed Zhu S-P, Liu G, Wu X-T, Chen F-X, Liu J-Q, Zhou Z-H, Zhang J-F, Fei S-J (2013) The effect of phloretin on human γδ T cells killing colon cancer SW-1116 cells. Int Immunopharmacol 15(1):6–14PubMed
13.
go back to reference Nelson J, Falk R (1992) The efficacy of phloridzin and phloretin on tumor cell growth. Anticancer Res 13(6A):2287–2292 Nelson J, Falk R (1992) The efficacy of phloridzin and phloretin on tumor cell growth. Anticancer Res 13(6A):2287–2292
14.
go back to reference Kypta RM, Waxman J (2012) Wnt/β-catenin signalling in prostate cancer. Nature Reviews Urology 9(8):418–428PubMed Kypta RM, Waxman J (2012) Wnt/β-catenin signalling in prostate cancer. Nature Reviews Urology 9(8):418–428PubMed
15.
go back to reference Prasannaraj G, Sahi SV, Benelli G, Venkatachalam P (2017) Coating with active Phytomolecules enhances anticancer activity of bio-engineered ag Nanocomplex. J Clust Sci 28(4):2349–2367 Prasannaraj G, Sahi SV, Benelli G, Venkatachalam P (2017) Coating with active Phytomolecules enhances anticancer activity of bio-engineered ag Nanocomplex. J Clust Sci 28(4):2349–2367
16.
go back to reference Priyadharshini RI, Prasannaraj G, Geetha N, Venkatachalam P (2014) Microwave-mediated extracellular synthesis of metallic silver and zinc oxide nanoparticles using macro-algae (Gracilaria edulis) extracts and its anticancer activity against human PC3 cell lines. Appl Biochem Biotechnol 174(8):2777–2790PubMed Priyadharshini RI, Prasannaraj G, Geetha N, Venkatachalam P (2014) Microwave-mediated extracellular synthesis of metallic silver and zinc oxide nanoparticles using macro-algae (Gracilaria edulis) extracts and its anticancer activity against human PC3 cell lines. Appl Biochem Biotechnol 174(8):2777–2790PubMed
17.
go back to reference Liu Y, Fan C, Pu L, Wei C, Jin H, Teng Y, Zhao M, Yu ACH, Jiang F, Shu J (2016) Phloretin induces cell cycle arrest and apoptosis of human glioblastoma cells through the generation of reactive oxygen species. J Neuro-Oncol 128(2):217–223 Liu Y, Fan C, Pu L, Wei C, Jin H, Teng Y, Zhao M, Yu ACH, Jiang F, Shu J (2016) Phloretin induces cell cycle arrest and apoptosis of human glioblastoma cells through the generation of reactive oxygen species. J Neuro-Oncol 128(2):217–223
18.
go back to reference Meyer F, Galan P, Douville P, Bairati I, Kegle P, Bertrais S, Estaquio C, Hercberg S (2005) Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU. VI. MAX trial. Int J Cancer 116(2):182–186PubMed Meyer F, Galan P, Douville P, Bairati I, Kegle P, Bertrais S, Estaquio C, Hercberg S (2005) Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU. VI. MAX trial. Int J Cancer 116(2):182–186PubMed
19.
go back to reference Kim J, Kim J, Bae J-S (2016) ROS homeostasis and metabolism: a critical liaison for cancer therapy. Exp Mol Med 48(11):e269PubMedPubMedCentral Kim J, Kim J, Bae J-S (2016) ROS homeostasis and metabolism: a critical liaison for cancer therapy. Exp Mol Med 48(11):e269PubMedPubMedCentral
20.
go back to reference Chang SN, Lee JM, Oh H, Park JH (2016) Glutathione peroxidase 3 inhibits prostate tumorigenesis in TRAMP mice. Prostate 76(15):1387–1398PubMed Chang SN, Lee JM, Oh H, Park JH (2016) Glutathione peroxidase 3 inhibits prostate tumorigenesis in TRAMP mice. Prostate 76(15):1387–1398PubMed
21.
go back to reference Lill R (2009) Function and biogenesis of iron–Sulphur proteins. Nature 460(7257):831–838PubMed Lill R (2009) Function and biogenesis of iron–Sulphur proteins. Nature 460(7257):831–838PubMed
22.
go back to reference Chen Y-F, Kao C-H, Chen Y-T, Wang C-H, Wu C-Y, Tsai C-Y, Liu F-C, Yang C-W, Wei Y-H, Hsu M-T (2009) Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice. Genes Dev 23(10):1183–1194PubMedPubMedCentral Chen Y-F, Kao C-H, Chen Y-T, Wang C-H, Wu C-Y, Tsai C-Y, Liu F-C, Yang C-W, Wei Y-H, Hsu M-T (2009) Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice. Genes Dev 23(10):1183–1194PubMedPubMedCentral
23.
go back to reference Chang NC, Nguyen M, Bourdon J, Risse P-A, Martin J, Danialou G, Rizzuto R, Petrof BJ, Shore GC (2012) Bcl-2-associated autophagy regulator Naf-1 required for maintenance of skeletal muscle. Hum Mol Genet 21(10):2277–2287PubMed Chang NC, Nguyen M, Bourdon J, Risse P-A, Martin J, Danialou G, Rizzuto R, Petrof BJ, Shore GC (2012) Bcl-2-associated autophagy regulator Naf-1 required for maintenance of skeletal muscle. Hum Mol Genet 21(10):2277–2287PubMed
24.
go back to reference Li S-M, Chen C-H, Chen Y-W, Yen Y-C, Fang W-T, Tsai F-Y, Chang J-L, Shen Y-Y, Huang S-F, Chuu C-P (2017) Upregulation of CISD2 augments ROS homeostasis and contributes to tumorigenesis and poor prognosis of lung adenocarcinoma. Sci Rep 7(1):11893PubMedPubMedCentral Li S-M, Chen C-H, Chen Y-W, Yen Y-C, Fang W-T, Tsai F-Y, Chang J-L, Shen Y-Y, Huang S-F, Chuu C-P (2017) Upregulation of CISD2 augments ROS homeostasis and contributes to tumorigenesis and poor prognosis of lung adenocarcinoma. Sci Rep 7(1):11893PubMedPubMedCentral
25.
go back to reference Ouyang X, DeWeese TL, Nelson WG, Abate-Shen C (2005) Loss-of-function of Nkx3. 1 promotes increased oxidative damage in prostate carcinogenesis. Cancer Res 65(15):6773–6779PubMed Ouyang X, DeWeese TL, Nelson WG, Abate-Shen C (2005) Loss-of-function of Nkx3. 1 promotes increased oxidative damage in prostate carcinogenesis. Cancer Res 65(15):6773–6779PubMed
26.
go back to reference Prendergast GC (1999) Mechanisms of apoptosis by c-Myc. Oncogene 18(19):2967–2987PubMed Prendergast GC (1999) Mechanisms of apoptosis by c-Myc. Oncogene 18(19):2967–2987PubMed
27.
go back to reference Cassinelli G, Supino R, Zuco V, Lanzi C, Scovassi AI, Semple SC, Zunino F (2004) Role of c-myc protein in hormone refractory prostate carcinoma: cellular response to paclitaxel. Biochem Pharmacol 68(5):923–931PubMed Cassinelli G, Supino R, Zuco V, Lanzi C, Scovassi AI, Semple SC, Zunino F (2004) Role of c-myc protein in hormone refractory prostate carcinoma: cellular response to paclitaxel. Biochem Pharmacol 68(5):923–931PubMed
28.
29.
go back to reference Gajula RP, Chettiar ST, Williams RD, Thiyagarajan S, Kato Y, Aziz K, Wang R, Gandhi N, Wild AT, Vesuna F (2013) The twist box domain is required for Twist1-induced prostate cancer metastasis. Molecular Cancer Research:molcanres. 0218.2013 Gajula RP, Chettiar ST, Williams RD, Thiyagarajan S, Kato Y, Aziz K, Wang R, Gandhi N, Wild AT, Vesuna F (2013) The twist box domain is required for Twist1-induced prostate cancer metastasis. Molecular Cancer Research:molcanres. 0218.2013
Metadata
Title
Phloretin Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species
Authors
Ukjin Kim
C-Yoon Kim
Ji Min Lee
Hanseul Oh
Bokyeong Ryu
Jin Kim
Jae-Hak Park
Publication date
01-04-2020
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 2/2020
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-019-00643-y

Other articles of this Issue 2/2020

Pathology & Oncology Research 2/2020 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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