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

Abstract

BackgroundThe 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.MethodsCancer 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.ResultsPEITC 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.ConclusionsThe 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.

Phenethyl isothiocyanate inhibits colorectal cancer stem cells by suppressing Wnt/β‐catenin pathway

“…Many studies have reported that Wnt/β‐catenin pathway plays a key role in the development of colorectal cancer (Neri et al, ), and increasing evidence has manifested the critical function of Wnt/β‐catenin pathway in CSCs (Mao et al, ). PEITC was reported to inhibit proliferation of CSCs enriched from human cervical HeLa cell line through death receptors 4 and 5 (Wang et al, ). A recent study found that PEITC decreased ALDH1 activity as well as β‐catenin expression in colorectal cancer (Pereira et al, ).…”

“…For examples, a recent study has shown that PEITC reverses multidrug resistance in human gastric cancer (Tang, Song, Liu, et al, ), and the combination of PEITC with cisplatin may become a promising therapeutic approach for malignant pleural mesothelioma (Denis, Cellerin, Gregoire, & Blanquart, ). PEITC was also reported to inhibit proliferation of CSCs enriched from human cervical HeLa cell line through death receptors 4 and 5 (Wang, Upadhyaya, Liu, Knudsen, & Dey, ). Nonetheless, the effects of PEITC on colorectal CSCs and the role of Wnt/β‐catenin pathway in the action remain unclear.…”

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

“…Moreover, both ITCs have also proved to exert anticancer effects and target CSCs of several solid tumors [26,27,28,29,30]. However, despite the recognized role of these ITCs in the modulation of several cellular processes in CRC cells related with tumor progression, little is known about the effect of these phytochemicals in CRC stem-like cells.…”

Pinostrobin inhibits proliferation and induces apoptosis in cancer stem-like cells through a reactive oxygen species-dependent mechanism

“…P Ntreatment resulted in a signicant decline in the expression of CD44 + and CD24 + in HeLa cells as well as HeLa-CSCs, although the extent of reduction was more in CSCs than that observed in parent HeLa cells. 48 These data thus demonstrate the potential of P N to inhibit the self-renewal activity of CSCs. The decreased expression of CSC-specic markers endorses cell death in P N -treated cells and a decrease in the high CD44 + population would inhibit tumor growth, metastasis and cause relapse.…”