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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Phenethyl isothiocyanate upregulates death receptors 4 and 5 and inhibits proliferation in human cancer stem-like cells

Authors: Dan Wang, Bijaya Upadhyaya, Yi Liu, David Knudsen, Moul Dey

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

The cytokine TRAIL (tumor necrotic factor-related apoptosis-inducing ligand) selectively induces apoptosis in cancer cells, but cancer stem cells (CSCs) that contribute to cancer-recurrence are frequently TRAIL-resistant. Here we examined hitherto unknown effects of the dietary anti-carcinogenic compound phenethyl isothiocyanate (PEITC) on attenuation of proliferation and tumorigenicity and on up regulation of death receptors and apoptosis in human cervical CSC.

Methods

Cancer stem-like cells were enriched from human cervical HeLa cell line by sphere-culture method and were characterized by CSC-specific markers’ analyses (flow cytometry) and Hoechst staining. Cell proliferation assays, immunoblotting, and flow cytometry were used to assess anti-proliferative as well as pro-apoptotic effects of PEITC exposure in HeLa CSCs (hCSCs). Xenotransplantation study in a non-obese diabetic, severe combined immunodeficient (NOD/SCID) mouse model, histopathology, and ELISA techniques were further utilized to validate our results in vivo.

Results

PEITC attenuated proliferation of CD44high/+/CD24low/–, stem-like, sphere-forming subpopulations of hCSCs in a concentration- and time-dependent manner that was comparable to the CSC antagonist salinomycin. PEITC exposure-associated up-regulation of cPARP (apoptosis-associated cleaved poly [ADP-ribose] polymerase) levels and induction of DR4 and DR5 (death receptor 4 and 5) of TRAIL signaling were observed. Xenotransplantation of hCSCs into mice resulted in greater tumorigenicity than HeLa cells, which was diminished along with serum hVEGF-A (human vascular endothelial growth factor A) levels in the PEITC-pretreated hCSC group. Lung metastasis was observed only in the hCSC-injected group that did not receive PEITC-pretreatment.

Conclusions

The anti-proliferative effects of PEITC in hCSCs may at least partially result from up regulation of DR4 and possibly DR5 of TRAIL-mediated apoptotic pathways. PEITC may offer a novel approach for improving therapeutic outcomes in cancer patients.
Appendix
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Literature
1.
Liu MT, Huang WT, Wang AY, Huang CC, Huang CY, Chang TH, Pi CP, Yang HH: Prediction of outcome of patients with metastatic breast cancer: evaluation with prognostic factors and Nottingham prognostic index. Support Care Cancer. 2010, 18 (12): 1553-1564.CrossRefPubMed
2.
Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM: Cancer stem cells–perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res. 2006, 66 (19): 9339-9344.CrossRefPubMed
3.
Chen K, Huang YH, Chen JL: Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin. 2013, 34 (6): 732-740.CrossRefPubMedPubMedCentral
4.
Reya T, Morrison SJ, Clarke MF, Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 2001, 414 (6859): 105-111.CrossRefPubMed
5.
Gu W, Yeo E, McMillan N, Yu C: Silencing oncogene expression in cervical cancer stem-like cells inhibits their cell growth and self-renewal ability. Cancer Gene Ther. 2011, 18 (12): 897-905.CrossRefPubMed
6.
Fenwick GR, Heaney RK, Mullin WJ: Glucosinolates and their breakdown products in food and food plants. Crit Rev Food Sci Nutr. 1983, 18 (2): 123-201.CrossRefPubMed
7.
Dey M, Ripoll C, Pouleva R, Dorn R, Aranovich I, Zaurov D, Kurmukov A, Eliseyeva M, Belolipov I, Akimaliev A, Sodombekov I, Akimaliev D, Lila MA, Raskin I: Plant extracts from central Asia showing antiinflammatory activities in gene expression assays. Phytother Res. 2008, 22 (7): 929-934.CrossRefPubMed
8.
Dey M, Kuhn P, Ribnicky D, Premkumar V, Reuhl K, Raskin I: Dietary phenethylisothiocyanate attenuates bowel inflammation in mice. BMC Chem Biol. 2010, 10: 4-CrossRefPubMedPubMedCentral
9.
Liu Y, Chakravarty S, Dey M: Phenethylisothiocyanate alters site- and promoter-specific histone tail modifications in cancer cells. PLoS One. 2013, 8 (5): e64535-CrossRefPubMedPubMedCentral
10.
Mukherjee S, Bhattacharya RK, Roy M: Targeting protein kinase C (PKC) and telomerase by phenethyl isothiocyanate (PEITC) sensitizes PC-3 cells towards chemotherapeutic drug-induced apoptosis. J Environ Pathol Toxicol Oncol. 2009, 28 (4): 269-282.CrossRefPubMed
11.
Kang L, Wang ZY: Breast cancer cell growth inhibition by phenethyl isothiocyanate is associated with down-regulation of oestrogen receptor-alpha36. J Cell Mol Med. 2010, 14 (6B): 1485-1493.CrossRefPubMed
12.
le Huong D, Shim JH, Choi KH, Shin JA, Choi ES, Kim HS, Lee SJ, Kim SJ, Cho NP, Cho SD: Effect of beta-phenylethyl isothiocyanate from cruciferous vegetables on growth inhibition and apoptosis of cervical cancer cells through the induction of death receptors 4 and 5. J Agric Food Chem. 2011, 59 (15): 8124-8131.CrossRefPubMed
13.
Wang X, Govind S, Sajankila SP, Mi L, Roy R, Chung FL: Phenethyl isothiocyanate sensitizes human cervical cancer cells to apoptosis induced by cisplatin. Mol Nutr Food Res. 2011, 55 (10): 1572-1581.CrossRefPubMedPubMedCentral
14.
Satyan KS, Swamy N, Dizon DS, Singh R, Granai CO, Brard L: Phenethyl isothiocyanate (PEITC) inhibits growth of ovarian cancer cells by inducing apoptosis: role of caspase and MAPK activation. Gynecol Oncol. 2006, 103 (1): 261-270.CrossRefPubMed
15.
Nishikawa A, Furukawa F, Lee IS, Tanaka T, Hirose M: Potent chemopreventive agents against pancreatic cancer. Curr Cancer Drug Targets. 2004, 4 (4): 373-384.CrossRefPubMed
16.
NCI: Clinical development plan: phenethyl isothiocyanate. J Cell Biochem Suppl. 1996, 26: 149-157.
17.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010, 127 (12): 2893-2917.CrossRefPubMed
18.
19.
Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA, Goodwin RG: Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995, 3 (6): 673-682.CrossRefPubMed
20.
Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC, Lynch DH: Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med. 1999, 5 (2): 157-163.CrossRefPubMed
21.
Falschlehner C, Emmerich CH, Gerlach B, Walczak H: TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol. 2007, 39 (7–8): 1462-1475.CrossRefPubMed
22.
Soldani C, Scovassi AI: Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: an update. Apoptosis. 2002, 7 (4): 321-328.CrossRefPubMed
23.
Koschny R, Walczak H, Ganten TM: The promise of TRAIL–potential and risks of a novel anticancer therapy. J Mol Med (Berl). 2007, 85 (9): 923-935.CrossRef
24.
Nimmanapalli R, Perkins CL, Orlando M, O'Bryan E, Nguyen D, Bhalla KN: Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. Cancer Res. 2001, 61 (2): 759-763.PubMed
25.
Naka T, Sugamura K, Hylander BL, Widmer MB, Rustum YM, Repasky EA: Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with chemotherapeutic agents on patients' colon tumors grown in SCID mice. Cancer Res. 2002, 62 (20): 5800-5806.PubMed
26.
Yin S, Xu L, Bandyopadhyay S, Sethi S, Reddy KB: Cisplatin and TRAIL enhance breast cancer stem cell death. Int J Oncol. 2011, 39 (4): 891-898.PubMedPubMedCentral
27.
Wicker CA, Sahu RP, Kulkarni-Datar K, Srivastava SK, Brown TL: BITC sensitizes pancreatic adenocarcinomas to TRAIL-induced apoptosis. Cancer Growth Metastasis. 2010, 2009 (2): 45-55.PubMedPubMedCentral
28.
Kim H, Kim EH, Eom YW, Kim WH, Kwon TK, Lee SJ, Choi KS: Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant hepatoma cells to TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of DR5. Cancer Res. 2006, 66 (3): 1740-1750.CrossRefPubMed
29.
Matsui TA, Sowa Y, Yoshida T, Murata H, Horinaka M, Wakada M, Nakanishi R, Sakabe T, Kubo T, Sakai T: Sulforaphane enhances TRAIL-induced apoptosis through the induction of DR5 expression in human osteosarcoma cells. Carcinogenesis. 2006, 27 (9): 1768-1777.CrossRefPubMed
30.
Liebes L, Conaway CC, Hochster H, Mendoza S, Hecht SS, Crowell J, Chung FL: High-performance liquid chromatography-based determination of total isothiocyanate levels in human plasma: application to studies with 2-phenethyl isothiocyanate. Anal Biochem. 2001, 291 (2): 279-289.CrossRefPubMed
31.
Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES: Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009, 138 (4): 645-659.CrossRefPubMedPubMedCentral
32.
Scharenberg CW, Harkey MA, Torok-Storb B: The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood. 2002, 99 (2): 507-512.CrossRefPubMed
33.
Luna LG: Routine staining procedure. Manual of Histologic staining methods of the armed forces. Edited by: Luna LG. 1968, New York: McGraw-Hill Book Company, Blakiston Division, 32-39. 3
34.
Jordan MA, Wendell K, Gardiner S, Derry WB, Copp H, Wilson L: Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res. 1996, 56 (4): 816-825.PubMed
35.
Angioli R, Luvero D, Aloisi A, Capriglione S, Gennari P, Linciano F, Li Destri M, Scaletta G, Montera R, Plotti F: Adjuvant chemotherapy after primary treatments for cervical cancer: a critical point of view and review of the literature. Expert Rev Anticancer Ther. 2014, 14 (4): 431-439.CrossRefPubMed
36.
Richardson MA: Biopharmacologic and herbal therapies for cancer: research update from NCCAM. J Nutr. 2001, 131 (11 Suppl): 3037S-3040S.PubMed
37.
38.
Li M, Knight DA, Smyth MJ, Stewart TJ: Sensitivity of a novel model of mammary cancer stem cell-like cells to TNF-related death pathways. Cancer Immunol Immunother. 2012, 61 (8): 1255-1268.CrossRefPubMed
39.
Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A: Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science. 1997, 277 (5327): 818-821.CrossRefPubMed
40.
Johnstone RW, Frew AJ, Smyth MJ: The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer. 2008, 8 (10): 782-798.CrossRefPubMed
41.
Rushworth SA, Micheau O: Molecular crosstalk between TRAIL and natural antioxidants in the treatment of cancer. Br J Pharmacol. 2009, 157 (7): 1186-1188.CrossRefPubMedPubMedCentral
42.
Yu R, Mandlekar S, Harvey KJ, Ucker DS, Kong AN: Chemopreventive isothiocyanates induce apoptosis and caspase-3-like protease activity. Cancer Res. 1998, 58 (3): 402-408.PubMed
43.
Dey M, Ribnicky D, Kurmukov AG, Raskin I: In vitro and in vivo anti-inflammatory activity of a seed preparation containing phenethylisothiocyanate. J Pharmacol Exp Ther. 2006, 317 (1): 326-333.CrossRefPubMed
44.
Fiers W: Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level. FEBS Lett. 1991, 285 (2): 199-212.CrossRefPubMed
45.
Kim K, Fisher MJ, Xu SQ, el-Deiry WS: Molecular determinants of response to TRAIL in killing of normal and cancer cells. Clin Cancer Res. 2000, 6 (2): 335-346.PubMed
Metadata
Title
Phenethyl isothiocyanate upregulates death receptors 4 and 5 and inhibits proliferation in human cancer stem-like cells
Authors
Dan Wang
Bijaya Upadhyaya
Yi Liu
David Knudsen
Moul Dey
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-591

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