Cancer stem cells (CSCs) are responsible for colorectal cancer (CRC) initiation, growth, and metastasis. Garlic-derived organosulfur compound diallyl trisulfide (DATS) possesses cancer suppressive properties. Wnt/β-catenin signaling is a key target for CSCs inhibition. However, the interventional effect of DATS on colorectal CSCs has not been clarified. We aimed to illustrate the regulation of Wnt/β-catenin in DATS-induced colorectal CSCs inhibition.
Serum-free medium culture was used to enrich colorectal CSCs. SW480 and DLD-1 sphere-forming cells were treated with different concentrations of DATS for 5 days; LiCl and β-catenin plasmids were used to stimulate the activity of Wnt/β-catenin pathway. The size and number of colonspheres were detected by tumorsphere formation assay; the expression of colorectal CSCs-related genes was detected by Western blotting and qRT-PCR; the capacities of colorectal CSCs proliferation and apoptosis were detected by Cell Counting Kit-8, Hoechst 33258 cell staining and flow cytometry, respectively.
The levels of colorectal CSCs markers were elevated in the tumorspheres cells. DATS efficiently suppressed the activity of colorectal CSCs, as evidenced by reducing the size and number of colonspheres, decreasing the expression of colorectal CSCs markers, promoting apoptosis and inhibiting the proliferation of colorectal CSCs. Moreover, DATS suppressed the activity of Wnt/β-catenin pathway, while upregulation of Wnt/β-catenin diminished the inhibitory effect of DATS on colorectal CSCs.
Wnt/β-catenin pathway mediates DATS-induced colorectal CSCs suppression. These findings support the use of DATS for targeting colorectal CSCs.
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Siegel RL, Miller KD, Jemal A (2017) Cancer statistics 2017. CA Cancer J Clin 67(1):7–30
Torre LA et al (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108
Miller KD et al (2016) Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 66(4):271–289
Thomassen I et al (2013) Incidence, prognosis, and treatment options for patients with synchronous peritoneal carcinomatosis and liver metastases from colorectal origin. Dis Colon Rectum 56(12):1373–1380
Frank NY, Schatton T, Frank MH (2010) The therapeutic promise of the cancer stem cell concept. J Clin Invest 120(1):41–50
Islam F et al (2015) Cancer stem cell: fundamental experimental pathological concepts and updates. Exp Mol Pathol 98(2):184–191
O’Brien CA et al (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110
Dalerba P et al (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 104(24):10158–10163
Clarke MF et al (2006) Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 66(19):9339–9344
Huang EH, Wicha MS (2008) Colon cancer stem cells: implications for prevention and therapy. Trends Mol Med 14(11):503–509
Zeuner A et al (2014) Colorectal cancer stem cells: from the crypt to the clinic. Cell Stem Cell 15(6):692–705
Holland JD et al (2013) Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol 25(2):254–264
Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3):469–480
Tang X et al (2017) Upregulation of GNL3 expression promotes colon cancer cell proliferation, migration, invasion and epithelial-mesenchymal transition via the Wnt/beta-catenin signaling pathway. Oncol Rep 38(4):2023–2032
Wang G et al (2017) Cyclophilin A maintains glioma-initiating cell stemness by regulating Wnt/beta-catenin signaling. Clin Cancer Res 23(21):6640–6649
Lai KC et al (2013) Diallyl sulfide, diallyl disulfide, and diallyl trisulfide inhibit migration and invasion in human colon cancer colo 205 cells through the inhibition of matrix metalloproteinase-2, -7, and -9 expressions. Environ Toxicol 28(9):479–488
Wang HC et al (2017) Diallyl trisulfide inhibits cell migration and invasion of human melanoma a375 cells via inhibiting integrin/facal adhesion kinase pathway. Environ Toxicol 32(11):2352–2359
Jiang XY et al (2017) Diallyl trisulfide suppresses tumor growth through the attenuation of Nrf2/Akt and activation of p38/JNK and potentiates cisplatin efficacy in gastric cancer treatment. Acta Pharmacol Sin 38(7):1048–1058
Yu CS et al (2012) Diallyl trisulfide induces apoptosis in human primary colorectal cancer cells. Oncol Rep 28(3):949–954
Wu PP et al (2011) Diallyl trisulfide (DATS) inhibits mouse colon tumor in mouse CT-26 cells allograft model in vivo. Phytomedicine 18(8–9):672–676
Dotse E, Bian Y (2016) Isolation of colorectal cancer stem-like cells. Cytotechnology 68(4):609–619
Melin C et al (2014) Sedimentation field flow fractionation monitoring of in vitro enrichment in cancer stem cells by specific serum-free culture medium. J Chromatogr B Analyt Technol Biomed Life Sci 963:40–46
Boman BM, Wicha MS (2008) Cancer stem cells: a step toward the cure. J Clin Oncol 26(17):2795–2799
Wicha MS, Liu SL, Dontu G (2006) Cancer stem cells: an old idea—a paradigm shift. Can Res 66(4):1883–1890
Ricci-Vitiani L et al (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115
Kozovska Z, Gabrisova V, Kucerova L (2014) Colon cancer: cancer stem cells markers, drug resistance and treatment. Biomed Pharmacother 68(8):911–916
Du L et al (2008) CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res 14(21):6751–6760
Cho SH et al (2012) CD44 enhances the epithelial-mesenchymal transition in association with colon cancer invasion. Int J Oncol 41(1):211–218
Huang EH et al (2009) Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Can Res 69(8):3382–3389
Carpentino JE et al (2009) Aldehyde dehydrogenase-expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer Res 69(20):8208–8215
Kashyap V et al (2009) Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells Dev 18(7):1093–1108
Amini S et al (2014) The expressions of stem cell markers: Oct4, Nanog, Sox2, nucleostemin, Bmi, Zfx, Tcl1, Tbx3, Dppa4, and Esrrb in bladder, colon, and prostate cancer, and certain cancer cell lines. Anat Cell Biol 47(1):1–11
Wang L et al (2014) Enrichment and characterization of cancer stemlike cells from a cervical cancer cell line. Mol Med Rep 9(6):2117–2123
Hashimoto N et al (2014) Cancer stem-like sphere cells induced from de-differentiated hepatocellular carcinoma-derived cell lines possess the resistance to anti-cancer drugs. BMC Cancer 14:722
Zhu YT et al (2016) A modified method by differential adhesion for enrichment of bladder cancer stem cells. Int Braz J Urol 42(4):817–824
Wang L et al (2013) Enrichment of prostate cancer stem-like cells from human prostate cancer cell lines by culture in serum-free medium and chemoradiotherapy. Int J Biol Sci 9(5):472–479
Li Y et al (2010) Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 16(9):2580–2590
Marquardt JU et al (2015) Curcumin effectively inhibits oncogenic NF-kappaB signaling and restrains stemness features in liver cancer. J Hepatol 63(3):661–669
Zhu J et al (2017) Wnt/beta-catenin pathway mediates (−)-Epigallocatechin-3-gallate (EGCG) inhibition of lung cancer stem cells. Biochem Biophys Res Commun 482(1):15–21
Lim KJ et al (2011) A polymeric nanoparticle formulation of curcumin inhibits growth, clonogenicity and stem-like fraction in malignant brain tumors. Cancer Biol Ther 11(5):464–473
Zhao C et al (2007) Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12(6):528–541
Zhu J et al (2017) miR-19 targeting of GSK3beta mediates sulforaphane suppression of lung cancer stem cells. J Nutr Biochem 44:80–91
Chikazawa N et al (2010) Inhibition of Wnt signaling pathway decreases chemotherapy-resistant side-population colon cancer cells. Anticancer Res 30(6):2041–2048
This work was supported by grants from the National Natural Science Foundation of China (No. 81573139, No. 81373005, No. 81602839), the National Basic Research Program of China (973 Program) (No. 2013CB910303), and by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
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This article does not contain any studies with human participants or animals performed by any of the authors.
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Zhang, Q., Li, XT., Chen, Y. et al. Wnt/β-catenin signaling mediates the suppressive effects of diallyl trisulfide on colorectal cancer stem cells. Cancer Chemother Pharmacol 81, 969–977 (2018). https://doi.org/10.1007/s00280-018-3565-0
- Diallyl trisulfide
- Colorectal cancer stem cells
- Wnt/β-catenin signaling