Dietary flavonoid tangeretin induces reprogramming of epithelial to mesenchymal transition in prostate cancer cells by targeting the PI3K/Akt/mTOR signaling pathway

Zhu,Wen‑Bin; Xiao,Ning; Liu,Xing‑Jie

doi:10.3892/ol.2017.7307

Dietary flavonoid tangeretin induces reprogramming of epithelial to mesenchymal transition in prostate cancer cells by targeting the PI3K/Akt/mTOR signaling pathway

Authors:
- Wen‑Bin Zhu
- Ning Xiao
- Xing‑Jie Liu
View Affiliations

Affiliations: Department of Urology, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China, Department of Obstetrics and Gynecology, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
Published online on: October 31, 2017 https://doi.org/10.3892/ol.2017.7307
Pages: 433-440

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Tangeretin, a natural polymethoxyflavone present in the peel of citrus fruits is known to exhibit anticancer properties against a variety of carcinomas. Previous experimental evidence suggests that lifestyle and dietary habits affect the risk of prostate cancer to a certain extent. As the effect of tangeretin on prostate cancer is unexplored, the present study investigated the effect of tangeretin on androgen‑insensitive PC‑3 cells and androgen‑sensitive LNCaP cells. Tangeretin reduced the cell viability of PC‑3 cells in a dose‑ and time‑dependent manner, with the half‑maximal inhibitory concentration (IC50) observed at 75 µM dose following 72 h of incubation, while in LNCaP cells, the IC50 was identified to be ~65 µM. Expression levels of the mesenchymal proteins including vimentin, cluster of differentiation 44 and Neural cadherin in PC‑3 cells were reduced by tangeretin treatment, whereas those of the epithelial proteins, including Epithelial cadherin and cytokeratin‑19 were upregulated. Treatment of PC‑3 cells also resulted in the downregulation of the phosphoinositide 3‑kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. Therefore, it may be concluded that tangeretin induces reprogramming of epithelial‑mesenchymal transition in PC‑3 cells by targeting the PI3K/Akt/mTOR signaling pathway.

View Figures

View References

1	Shelke AR and Mohile SG: Treating prostate cancer in elderly men: How does aging affect the outcome? Curr Treat Options Oncol. 12:263–275. 2011. View Article : Google Scholar : PubMed/NCBI
2	Crawford ED: Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology. 73(5 Suppl): S4–S10. 2009. View Article : Google Scholar : PubMed/NCBI
3	Bosland MC: The role of steroid hormones in prostate carcinogenesis. J Natl Cancer Inst Monogr. 1–66. 2000.PubMed/NCBI
4	Crawford ED: Prostate cancer. Introduction. Urology. 62(6 Suppl 1): S1–S2. 2003. View Article : Google Scholar
5	Grönberg H: Prostate cancer epidemiology. Lancet. 361:859–864. 2003. View Article : Google Scholar : PubMed/NCBI
6	Crawford ED: Epidemiology of prostate cancer. Urology. 62(6 Suppl 1): S3–S12. 2003. View Article : Google Scholar
7	Whittemore AS, Kolonel LN, Wu AH, John EM, Gallagher RP, Howe GR, Burch JD, Hankin J, Dreon DM, West DW, et al: Prostate cancer in relation to diet, physical activity, and body size in blacks, whites, and Asians in the United States and Canada. J Natl Cancer Inst. 87:652–661. 1995. View Article : Google Scholar : PubMed/NCBI
8	Gravdal K, Halvorsen OJ, Haukaas SA and Akslen LA: A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res. 13:7003–7011. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI
10	Tomita K, van Bokhoven A, van Leenders GJ, Ruijter ET, Jansen CF, Bussemakers MJ and Schalken JA: Cadherin switching in human prostate cancer progression. Cancer Res. 60:3650–3654. 2000.PubMed/NCBI
11	Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, Kim JK, Patel LR, Ying C, Ziegler AM, et al: Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 121:1298–1312. 2011. View Article : Google Scholar : PubMed/NCBI
12	Steeg PS: Cancer biology: Emissaries set up new sites. Nature. 438:750–751. 2005. View Article : Google Scholar : PubMed/NCBI
13	Alexander NR, Tran NL, Rekapally H, Summers CE, Glackin C and Heimark RL: N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1. Cancer Res. 66:3365–3369. 2006. View Article : Google Scholar : PubMed/NCBI
14	Collins AT, Berry PA, Hyde C, Stower MJ and Maitland NJ: Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65:10946–10951. 2005. View Article : Google Scholar : PubMed/NCBI
15	Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S and Sarkar FH: Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One. 5:e124452010. View Article : Google Scholar : PubMed/NCBI
16	Maitland NJ and Collins A: A tumour stem cell hypothesis for the origins of prostate cancer. BJU Int. 96:1219–1223. 2005. View Article : Google Scholar : PubMed/NCBI
17	Pavese JM and Bergan RC: Circulating tumor cells exhibit a biologically aggressive cancer phenotype accompanied by selective resistance to chemotherapy. Cancer Lett. 352:179–186. 2014. View Article : Google Scholar : PubMed/NCBI
18	Sak K: Site-specific anticancer effects of dietary flavonoid quercetin. Nutr Cancer. 66:177–193. 2014. View Article : Google Scholar : PubMed/NCBI
19	Sak K: Cytotoxicity of dietary flavonoids on different human cancer types. Pharmacogn Rev. 8:122–146. 2014. View Article : Google Scholar : PubMed/NCBI
20	Gupta S, Afaq F and Mukhtar H: Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of tangeretin in normal versus human prostate carcinoma cells. Biochem Biophys Res Commun. 287:914–920. 2001. View Article : Google Scholar : PubMed/NCBI
21	Pan MH, Chen WJ, Lin-Shiau SY, Ho CT and Lin JK: Tangeretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis. 23:1677–1684. 2002. View Article : Google Scholar : PubMed/NCBI
22	el SA Arafa, Zhu Q, Barakat BM, Wani G, Zhao Q, El-Mahdy MA and Wani AA: Tangeretin sensitizes cisplatin-resistant human ovarian cancer cells through downregulation of phosphoinositide 3-kinase/Akt signaling pathway. Cancer Res. 69:8910–8917. 2009. View Article : Google Scholar : PubMed/NCBI
23	Dong Y, Cao A, Shi J, Yin P, Wang L, Ji G, Xie J and Wu D: Tangeretin, a citrus polymethoxyflavonoid, induces apoptosis of human gastric cancer AGS cells through extrinsic and intrinsic signaling pathways. Oncol Rep. 31:1788–1794. 2014. View Article : Google Scholar : PubMed/NCBI
24	Lakshmi A and Subramanian S: Chemotherapeutic effect of tangeretin, a polymethoxylated flavone studied in 7, 12-dimethylbenz(a)anthracene induced mammary carcinoma in experimental rats. Biochimie. 99:96–109. 2014. View Article : Google Scholar : PubMed/NCBI
25	Periyasamy K, Baskaran K, Ilakkia A, Vanitha K, Selvaraj S and Sakthisekaran D: Antitumor efficacy of tangeretin by targeting the oxidative stress mediated on 7,12-dimethylbenz(a) anthracene-induced proliferative breast cancer in Sprague-Dawley rats. Cancer Chemother Pharmacol. 75:263–272. 2015. View Article : Google Scholar : PubMed/NCBI
26	Das A, Bhattacharya A, Chakrabarty S, Ganguli A and Chakrabarti G: Smokeless tobacco extract (STE)-induced toxicity in mammalian cells is mediated by the disruption of cellular microtubule network: A key mechanism of cytotoxicity. PLoS One. 8:e682242013. View Article : Google Scholar : PubMed/NCBI
27	Balint K, Xiao M, Pinnix CC, Soma A, Veres I, Juhasz I, Brown EJ, Capobianco AJ, Herlyn M and Liu ZJ: Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression. J Clin Invest. 115:3166–3176. 2005. View Article : Google Scholar : PubMed/NCBI
28	Di Cello F, Flowers VL, Li H, Vecchio-Pagán B, Gordon B, Harbom K, Shin J, Beaty R, Wang W, Brayton C, et al: Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells. Mol Cancer. 12:902013. View Article : Google Scholar : PubMed/NCBI
29	Tanno B, Sesti F, Cesi V, Bossi G, Ferrari-Amorotti G, Bussolari R, Tirindelli D, Calabretta B and Raschellà G: Expression of Slug is regulated by c-Myb and is required for invasion and bone marrow homing of cancer cells of different origin. J Biol Chem. 285:29434–29445. 2010. View Article : Google Scholar : PubMed/NCBI
30	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
31	Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ, Kearsley JH and Li Y: Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis. 4:e8752013. View Article : Google Scholar : PubMed/NCBI
32	Ni J, Cozzi P, Hao J, Beretov J, Chang L, Duan W, Shigdar S, Delprado W, Graham P, Bucci J, et al: Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway. Int J Biochem Cell Biol. 45:2736–2748. 2013. View Article : Google Scholar : PubMed/NCBI
33	Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, et al: Integrative genomic profiling of human prostate cancer. Cancer Cell. 18:11–22. 2010. View Article : Google Scholar : PubMed/NCBI