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 language | English |
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Article number | 591 |
Journal | BMC Cancer |
Volume | 14 |
Issue number | 1 |
DOIs | |
State | Published - 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.
Funders | Funder number |
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SD-Agriculture Experiment Station | |
National Institutes of Health (NIH) | 3AH360 |
National Center for Complementary and Integrative Health | R00AT004245 |
Keywords
- Apoptosis
- Cancer stem cells
- Death receptors
- Phenethyl isothiocyanate
- TRAIL
ASJC Scopus subject areas
- Genetics
- Oncology
- Cancer Research