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

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

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish
Article number591
JournalBMC Cancer
Volume14
Issue number1
DOIs
StatePublished - 2014

Bibliographical note

Publisher Copyright:
© 2014 Wang et al.

Funding

We acknowledge Qingming Song for his help with mice work. Support for this work came from National Institutes of Health grant R00AT4245 and SD-Agriculture Experiment Station grant 3AH360 to MD. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

FundersFunder number
SD-Agriculture Experiment Station
National Institutes of Health (NIH)3AH360
National Center for Complementary and Integrative HealthR00AT004245

    Keywords

    • Apoptosis
    • Cancer stem cells
    • Death receptors
    • Phenethyl isothiocyanate
    • TRAIL

    ASJC Scopus subject areas

    • Genetics
    • Oncology
    • Cancer Research

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