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

35 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

Funding Information:
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.

Publisher Copyright:
© 2014 Wang et al.

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

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