Effect of β-carotene on cancer cell stemness and differentiation in SK-N-BE(2)C neuroblastoma cells

Lee,Hyun   Ah; Park,Seolhyun; Kim,Yuri

doi:10.3892/or.2013.2643

Effect of β-carotene on cancer cell stemness and differentiation in SK-N-BE(2)C neuroblastoma cells

Authors:
- Hyun Ah Lee
- Seolhyun Park
- Yuri Kim
View Affiliations

Affiliations: Department of Nutritional Science and Food Management, Ewha Womans University, Seodaemun-gu, Seoul 120-750, Republic of Korea
Published online on: July 30, 2013 https://doi.org/10.3892/or.2013.2643
Pages: 1869-1877

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

Neuroblastoma is a solid tumor often diagnosed in childhood. While there have been intense efforts to develop a treatment for neuroblastoma, current therapies remain unsuccessful due to high rate of resistance and metastasis. Most cancers originate from a subset of self-renewing cells, primarily cancer stem cells (CSCs), which establish a tumor through continuous self-renewal and differentiation. The successful elimination of CSCs is an important goal in the development of effective strategies to achieve complete remission for cancers. Although β-carotene has been associated with several anticancer mechanisms, the efficacy of β-carotene against CSCs remains unclear. In the present study, β-carotene was shown to reduce cell growth and induce neuronal cell differentiation, concomitant with a marked increase in the phosphorylation of extracellular signal-regulated kinases (ERK) (p42/p44). More importantly, β-carotene inhibited self-renewal characteristics of CSCs and decreased expression of several stem cell markers. Levels of mRNA and protein of Drosophila delta-like 1 homolog (Drosophila) (DLK1) were downregulated following treatment with β-carotene. In addition, knockdown of DLK1 by siRNA enhanced the inhibitory effect of β-carotene on colony formation of neuroblastoma cells. β-carotene also potentiated the effect of cisplatin on the self-renewal characteristics of CSCs in neuroblastoma, revealing that β-carotene has the capacity to resensitize cells to cisplatin cytotoxicity by directly targeting CSCs. In conclusion, β-carotene was shown to strongly increase the anticancer efficacy against neuroblastoma cancer stem-like cells. Moreover, these results suggest that the targeting of CSCs is a novel mechanism of β-carotene. Thus, β-carotene is a potential chemotherapeutic reagent for this cancer.

View Figures

View References

1	Brodeur GM: Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 3:203–216. 2003. View Article : Google Scholar : PubMed/NCBI
2	Ciccarone V, Spengler BA, Meyers MB, Biedler JL and Ross RA: Phenotypic diversification in human neuroblastoma cells: expression of distinct neural crest lineages. Cancer Res. 49:219–225. 1989.PubMed/NCBI
3	Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI
4	Clarke MF, Dick JE, Dirks PB, et al: Cancer stem cells - perspectives on current status and future directions: AACR Workshop on Cancer Stem cells. Cancer Res. 66:9339–9344. 2006. View Article : Google Scholar
5	Smas CM and Sul HS: Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation. Cell. 73:725–734. 1993. View Article : Google Scholar : PubMed/NCBI
6	Moore KA, Pytowski B, Witte L, Hicklin D and Lemischka IR: Hematopoietic activity of a stromal cell transmembrane protein containing epidermal growth factor-like repeat motifs. Proc Natl Acad Sci USA. 94:4011–4016. 1997. View Article : Google Scholar : PubMed/NCBI
7	Hunter T: Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell. 80:225–236. 1995. View Article : Google Scholar : PubMed/NCBI
8	Berwick DC, Calissano M, Corness JD, Cook SJ and Latchman DS: Regulation of Brn-3a N-terminal transcriptional activity by MEK1/2-ERK1/2 signalling in neural differentiation. Brain Res. 1256:8–18. 2009. View Article : Google Scholar : PubMed/NCBI
9	Ruiz-Hidalgo MJ, Gubina E, Tull L, Baladron V and Laborda J: dlk modulates mitogen-activated protein kinase signaling to allow or prevent differentiation. Exp Cell Res. 274:178–188. 2002. View Article : Google Scholar : PubMed/NCBI
10	Burdon T, Smith A and Savatier P: Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol. 12:432–438. 2002. View Article : Google Scholar : PubMed/NCBI
11	Mayne ST: Beta-carotene, carotenoids, and disease prevention in humans. FASEB J. 10:690–701. 1996.PubMed/NCBI
12	Comstock GW, Alberg AJ, Huang HY, et al: The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acids, carotenoids, α-tocopherol, selenium, and total peroxyl radical absorbing capacity. Am J Epidemiol. 168:831–840. 2008.PubMed/NCBI
13	Liu C, Russell RM and Wang XD: Low dose β-carotene supplementation of ferrets attenuates smoke-induced lung phosphorylation of JNK, p38 MAPK, and p53 proteins. J Nutr. 134:2705–2710. 2004.
14	Burton GW and Ingold KU: beta-Carotene: an unusual type of lipid antioxidant. Science. 224:569–573. 1984. View Article : Google Scholar : PubMed/NCBI
15	Tighe AP and Gudas LJ: Retinoic acid inhibits leukemia inhibitory factor signaling pathways in mouse embryonic stem cells. J Cell Physiol. 198:223–229. 2004. View Article : Google Scholar : PubMed/NCBI
16	Fenaux P, Chevret S, Guerci A, et al: Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group. Leukemia. 14:1371–1377. 2000. View Article : Google Scholar : PubMed/NCBI
17	Kakarala M, Brenner DE, Korkaya H, et al: Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat. 122:777–785. 2010. View Article : Google Scholar : PubMed/NCBI
18	Corrao S, Scaglione R, Arnone S and Licata G: Left ventricular diastolic filling alterations in subjects with mitral valve prolapse: a Doppler echocardiographic study. Eur Heart J. 14:369–372. 1993. View Article : Google Scholar : PubMed/NCBI
19	Denizot F and Lang R: Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods. 89:271–277. 1986. View Article : Google Scholar : PubMed/NCBI
20	Kim Y, Lin Q, Zelterman D and Yun Z: Hypoxia-regulated delta-like 1 homologue enhances cancer cell stemness and tumorigenicity. Cancer Res. 69:9271–9280. 2009. View Article : Google Scholar : PubMed/NCBI
21	Folkman J and Moscona A: Role of cell shape in growth control. Nature. 273:345–349. 1978. View Article : Google Scholar : PubMed/NCBI
22	Lin Q, Lee YJ and Yun Z: Differentiation arrest by hypoxia. J Biol Chem. 281:30678–30683. 2006. View Article : Google Scholar : PubMed/NCBI
23	Gross MD, Bishop TD, Belcher JD and Jacobs DR Jr: Induction of HL-60 cell differentiation by carotenoids. Nutr Cancer. 27:169–173. 1997. View Article : Google Scholar : PubMed/NCBI
24	Noguchi S, Sumida T, Ogawa H, Tada M and Takahata K: Effects of oxygenated carotenoid beta-cryptoxanthin on morphological differentiation and apoptosis in Neuro2a neuroblastoma cells. Biosci Biotechnol Biochem. 67:2467–2469. 2003. View Article : Google Scholar : PubMed/NCBI
25	Prasad KN, Carvalho E, Kentroti S, et al: Production of terminally differentiated neuroblastoma cells in culture. Restor Neurol Neurosci. 7:13–19. 1994.PubMed/NCBI
26	Favata MF, Horiuchi KY, Manos EJ, et al: Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 273:18623–18632. 1998. View Article : Google Scholar : PubMed/NCBI
27	Dang ZC and Lowik CW: Differential effects of PD98059 and U0126 on osteogenesis and adipogenesis. J Cell Biochem. 92:525–533. 2004. View Article : Google Scholar : PubMed/NCBI
28	Kim Y: Effect of retinoic acid and delta-like 1 homologue (DLK1) on differentiation in neuroblastoma. Nutr Res Pract. 4:276–282. 2010. View Article : Google Scholar : PubMed/NCBI
29	Wang XD and Krinsky NI: The bioconversion of beta-carotene into retinoids. Subcell Biochem. 30:159–180. 1998. View Article : Google Scholar : PubMed/NCBI
30	Floridon C, Jensen CH, Thorsen P, et al: Does fetal antigen 1 (FA1) identify cells with regenerative, endocrine and neuroendocrine potentials? A study of FA1 in embryonic, fetal, and placental tissue and in maternal circulation. Differentiation. 66:49–59. 2000. View Article : Google Scholar
31	Tornehave D, Jensen CH, Teisner B and Larsson LI: FA1 immunoreactivity in endocrine tumours and during development of the human fetal pancreas; negative correlation with glucagon expression. Histochem Cell Biol. 106:535–542. 1996. View Article : Google Scholar
32	Sakajiri S, O’Kelly J, Yin D, et al: Dlk1 in normal and abnormal hematopoiesis. Leukemia. 19:1404–1410. 2005. View Article : Google Scholar : PubMed/NCBI
33	Yin D, Xie D, Sakajiri S, et al: DLK1: increased expression in gliomas and associated with oncogenic activities. Oncogene. 25:1852–1861. 2006. View Article : Google Scholar : PubMed/NCBI
34	Ben-Porath I, Thomson MW, Carey VJ, et al: An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 40:499–507. 2008. View Article : Google Scholar : PubMed/NCBI
35	Phillips HS, Kharbanda S, Chen R, et al: Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 9:157–173. 2006. View Article : Google Scholar : PubMed/NCBI
36	Quasthoff S and Hartung HP: Chemotherapy-induced peripheral neuropathy. J Neurol. 249:9–17. 2002. View Article : Google Scholar
37	Huang H, Zhu L, Reid BR, Drobny GP and Hopkins PB: Solution structure of a cisplatin-induced DNA interstrand cross-link. Science. 270:1842–1845. 1995. View Article : Google Scholar : PubMed/NCBI
38	Donzelli E, Carfi M, Miloso M, et al: Neurotoxicity of platinum compounds: comparison of the effects of cisplatin and oxaliplatin on the human neuroblastoma cell line SH-SY5Y. J Neurooncol. 67:65–73. 2004. View Article : Google Scholar : PubMed/NCBI
39	Bruce AC: Cancer: Principles and practice of oncology. Anticancer Drugs. DeVita VT, Lawrence TS and Rosenberg SA: JB Lippincot Company; Washington: pp. 325–340. 1993
40	Teicher BA, Schwartz JL, Holden SA, Ara G and Northey D: In vivo modulation of several anticancer agents by beta-carotene. Cancer Chemother Pharmacol. 34:235–241. 1994. View Article : Google Scholar : PubMed/NCBI
41	Prasad KN, Hernandez C, Edwards-Prasad J, Nelson J, Borus T and Robinson WA: Modification of the effect of tamoxifen, cis-platin, DTIC, and interferon-α 2b on human melanoma cells in culture by a mixture of vitamins. Nutr Cancer. 22:233–245. 1994.PubMed/NCBI