Fenretinide targeting of human colon cancer sphere cells through cell cycle regulation and stress‑responsive activities

Liu,Lanlan; Liu,Jiansheng; Wang,Haiwei; Zhao,Hui; Du,Yanzhi

doi:10.3892/ol.2018.9296

Fenretinide targeting of human colon cancer sphere cells through cell cycle regulation and stress‑responsive activities

Authors:
- Lanlan Liu
- Jiansheng Liu
- Haiwei Wang
- Hui Zhao
- Yanzhi Du
View Affiliations

Affiliations: Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM)/Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, P.R. China, Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, P.R. China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, SAR, P.R. China
Published online on: August 13, 2018 https://doi.org/10.3892/ol.2018.9296
Pages: 5339-5348

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

Cancer stem cells (CSCs) are considered to be the main cause of chemoresistance and the resultant low survival rate of patients with cancer. N‑(4‑hydroxyphenyl)‑retinamide, known as fenretinide or 4HPR, is a synthetic derivative of all‑trans‑retinoic acid. It is a promising anticancer agent, has minimal side effects and synergizes with other anticancer agents to reinforce their anticancer efficacy. The present study investigated whether fenretinide eliminated colon sphere cells. HT29 and HCT116 cells incubated in low‑serum culture medium were more sensitive to fenretinide treatment than those incubated in full‑serum medium. Colon spheres formed in serum‑free medium demonstrated stem‑like characteristics. The percentage of cluster of differentiation (CD) 44+ cells was significantly higher in sphere cells compared with parental cells. Sphere cells also demonstrated increased tumorigenic ability in non‑obese diabetic/severe combined immunodeficiency mice. Fenretinide inhibited the formation of colon spheres in HT29 and HCT116 cells. Microarray, cell cycle and reverse transcription‑quantitative polymerase chain reaction analysis revealed that fenretinide induced genes associated with cell cycle regulation and the stress response in fenretinide‑treated HT29 sphere cells. To the best of our knowledge, the present study was the first to investigate the effect of fenretinide on colon stem cells. Fenretinide was demonstrated to preferentially target colon sphere cells, which may possess certain stem‑like characteristics. These results are an important addition to the current knowledge concerning fenretinide, and provide a foundation for its clinical application in the treatment of cancer.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Scopelliti A, Cammareri P, Catalano V, Saladino V, Todaro M and Stassi G: Therapeutic implications of cancer initiating cells. Expert Opin Biol Ther. 9:1005–1016. 2009. View Article : Google Scholar : PubMed/NCBI
3	Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C and De Maria R: Identification and expansion of human colon-cancer-initiating cells. Nature. 445:111–115. 2007. View Article : Google Scholar : PubMed/NCBI
4	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
5	Todaro M, Francipane MG, Medema JP and Stassi G: Colon cancer stem cells: Promise of targeted therapy. Gastroenterology. 138:2151–2162. 2010. View Article : Google Scholar : PubMed/NCBI
6	Moon RC, McCormick DL, Becci PJ, Shealy YF, Frickel F, Paust J and Sporn MB: Influence of 15 retinoic acid amides on urinary bladder carcinogenesis in the mouse. Carcinogenesis. 3:1469–1472. 1982. View Article : Google Scholar : PubMed/NCBI
7	Ohshima M, Ward JM and Wenk ML: Preventive and enhancing effects of retinoids on the development of naturally occurring tumors of skin, prostate gland, and endocrine pancreas in aged male ACI/segHapBR rats. J Natl Cancer Inst. 74:517–524. 1985.PubMed/NCBI
8	Malone W, Perloff M, Crowell J, Sigman C and Higley H: Fenretinide: A prototype cancer prevention drug. Expert Opin Investig Drugs. 12:1829–1842. 2003. View Article : Google Scholar : PubMed/NCBI
9	Du Y, Xia Y, Pan X, Chen Z, Wang A, Wang K, Li J and Zhang J: Fenretinide targets chronic myeloid leukemia stem/progenitor cells by regulation of redox signaling. Antioxid Redox Signal. 20:1866–1880. 2014. View Article : Google Scholar : PubMed/NCBI
10	Zhang H, Mi JQ, Fang H, Wang Z, Wang C, Wu L, Zhang B, Minden M, Yang WT, Wang HW, et al: Preferential eradication of acute myelogenous leukemia stem cells by fenretinide. Proc Natl Acad Sci USA. 110:5606–5611. 2013. View Article : Google Scholar : PubMed/NCBI
11	Lovat PE, Ranalli M, Bernassola F, Tilby M, Malcolm AJ, Pearson AD, Piacentini M, Melino G and Redfern CP: Distinct properties of fenretinide and CD437 lead to synergistic responses with chemotherapeutic reagents. Med Pediatr Oncol. 35:663–668. 2000. View Article : Google Scholar : PubMed/NCBI
12	Maurer BJ, Melton L, Billups C, Cabot MC and Reynolds CP: Synergistic cytotoxicity in solid tumor cell lines between N-(4-hydroxyphenyl)retinamide and modulators of ceramide metabolism. J Natl Cancer Inst. 92:1897–1909. 2000. View Article : Google Scholar : PubMed/NCBI
13	Shan D, Gopal AK and Press OW: Synergistic effects of the fenretinide (4-HPR) and anti-CD20 monoclonal antibodies on apoptosis induction of malignant human B cells. Clin Cancer Res. 7:2490–2495. 2001.PubMed/NCBI
14	Wang H, Zhang Y and Du Y: Ovarian and breast cancer spheres are similar in transcriptomic features and sensitive to fenretinide. Biomed Res Int. 2013:5109052013. View Article : Google Scholar : PubMed/NCBI
15	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
16	Lockhart DJ, Dong H, Byrne MC, Follettie MT, Gallo MV, Chee MS, Mittmann M, Wang C, Kobayashi M, Horton H and Brown EL: Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol. 14:1675–1680. 1996. View Article : Google Scholar : PubMed/NCBI
17	Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC and Lempicki RA: DAVID: Database for annotation, visualization, and integrated discovery. Genome Biol. 4:P32003. View Article : Google Scholar : PubMed/NCBI
18	Gene Ontology Consortium, . Gene ontology consortium: Going forward. Nucleic Acids Res. 43(Database Issue): D1049–D1056. 2015.PubMed/NCBI
19	Edgar R, Domrachev M and Lash AE: Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30:207–210. 2002. View Article : Google Scholar : PubMed/NCBI
20	Du Y, Wang K, Fang H, Li J, Xiao D, Zheng P, Chen Y, Fan H, Pan X, Zhao C, et al: Coordination of intrinsic, extrinsic, and endoplasmic reticulum-mediated apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid leukemia. Blood. 107:1582–1590. 2006. View Article : Google Scholar : PubMed/NCBI
21	Xiao L, Wang K, Teng Y and Zhang J: Component plane presentation integrated self-organizing map for microarray data analysis. FEBS Lett. 538:117–124. 2003. View Article : Google Scholar : PubMed/NCBI
22	Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ and Wicha MS: In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17:1253–1270. 2003. View Article : Google Scholar : PubMed/NCBI
23	Haraguchi N, Ohkuma M, Sakashita H, Matsuzaki S, Tanaka F, Mimori K, Kamohara Y, Inoue H and Mori M: CD133+CD44+ population efficiently enriches colon cancer initiating cells. Ann Surg Oncol. 15:2927–2933. 2008. View Article : Google Scholar : PubMed/NCBI
24	Du L, Wang H, He L, Zhang J, Ni B, Wang X, Jin H, Cahuzac N, Mehrpour M, Lu Y and Chen Q: CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res. 14:6751–6760. 2008. View Article : Google Scholar : PubMed/NCBI
25	Park CY, Tseng D and Weissman IL: Cancer stem cell-directed therapies: Recent data from the laboratory and clinic. Mol Ther. 17:219–230. 2009. View Article : Google Scholar : PubMed/NCBI
26	Gene Ontology Consortium, . The gene ontology project in 2008. Nucleic Acids Res. 36(Database Issue): D440–D444. 2008.PubMed/NCBI
27	Wang K, Fang H, Xiao D, Zhu X, He M, Pan X, Shi J, Zhang H, Jia X, Du Y and Zhang J: Converting redox signaling to apoptotic activities by stress-responsive regulators HSF1 and NRF2 in fenretinide treated cancer cells. PLoS One. 4:e75382009. View Article : Google Scholar : PubMed/NCBI
28	Szegezdi E, Logue SE, Gorman AM and Samali A: Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7:880–885. 2006. View Article : Google Scholar : PubMed/NCBI
29	Li X, Uemura K, Hashimoto T, Nasser-Ghodsi N, Arimon M, Lill CM, Palazzolo I, Krainc D, Hyman BT and Berezovska O: Neuronal activity and secreted amyloid β lead to altered amyloid β precursor protein and presenilin 1 interactions. Neurobiol Dis. 50:127–134. 2013. View Article : Google Scholar : PubMed/NCBI
30	Ward RJ and Dirks PB: Cancer stem cells: At the headwaters of tumor development. Annu Rev Pathol. 2:175–189. 2007. View Article : Google Scholar : PubMed/NCBI
31	Tang DG: Understanding cancer stem cell heterogeneity and plasticity. Cell Res. 22:457–472. 2012. View Article : Google Scholar : PubMed/NCBI
32	Kleffel S and Schatton T: Tumor dormancy and cancer stem cells: Two sides of the same coin? Adv Exp Med Biol. 734:145–179. 2013. View Article : Google Scholar : PubMed/NCBI
33	Shien K, Toyooka S, Ichimura K, Soh J, Furukawa M, Maki Y, Muraoka T, Tanaka N, Ueno T, Asano H, et al: Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy. Lung Cancer. 77:162–167. 2012. View Article : Google Scholar : PubMed/NCBI
34	Dean M, Fojo T and Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer. 5:275–284. 2005. View Article : Google Scholar : PubMed/NCBI
35	Jordan CT, Guzman ML and Noble M: Cancer stem cells. N Engl J Med. 355:1253–1261. 2006. View Article : Google Scholar : PubMed/NCBI
36	Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, et al: Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 458:780–783. 2009. View Article : Google Scholar : PubMed/NCBI
37	Hail N Jr, Kim HJ and Lotan R: Mechanisms of fenretinide-induced apoptosis. Apoptosis. 11:1677–1694. 2006. View Article : Google Scholar : PubMed/NCBI