Abstract
Breast cancer is the leading cause of cancer-related death for women. In breast cancer treatment, targeted therapy would be more effective and less harmful than radiotherapy or systemic chemotherapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in cancer cells but not in normal cells. Mesenchymal stem cells have shown great therapeutic potential in cancer therapy owing to their ability of homing to tumor sites and secreting many kinds of anti-tumor proteins including TRAIL. In this study, we found that IL-1β-stimulated human umbilical cord-derived mesenchymal stem cells (hUCMSCs) enhance the expression of membrane-bound and soluble TRAIL. Cellular FADD-like IL-1β-converting enzyme inhibitory protein (cFLIP) is an important regulator in TRAIL-mediated apoptosis and relates to TRAIL resistance in cancer cells. Previous studies have shown that embelin, which is extracted from Embelia ribes, can increase the TRAIL sensitivity of cancer cells by reducing cFLIP expression. Here we have demonstrated that cFLIPL is correlated with TRAIL-resistance and that embelin effectively downregulates cFLIPL in breast cancer cells. Moreover, co-culture of IL-1β-stimulated hUCMSCs with embelin-treated breast cancer cells could effectively induce apoptosis in breast cancer cells. The combined effects of embelin and IL-1β-stimulated hUCMSCs may provide a new therapeutic strategy for breast cancer therapy.
Highlights
According to the World Health Organization (WHO) report, breast cancer is the most common cancer in women and the leading cause of cancer-related death in w omen[1]
We further investigated whether treatment of IL-1β on human umbilical cord-derived mesenchymal stem cells (hUCMSCs) could increase the expression of soluble tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)
We found that embelin could upregulate DR4 and DR5 expression and enhance TRAIL-mediated apoptosis in breast cancer cell lines
Summary
According to the World Health Organization (WHO) report, breast cancer is the most common cancer in women and the leading cause of cancer-related death in w omen[1]. TNF-related apoptosis-inducing ligand (TRAIL) has been reported to induce apoptosis in different tumor cell lines including breast cancer but not normal cells[5,6]. Unlike hBMMSCs, human umbilical cord-derived mesenchymal stem cells (hUCMSCs) did not transform to TAFs in the presence of breast and ovarian c ancer[9]. The binding of ligand and receptor changes the Fas-associated death domain protein (FADD) to activate caspase-8/10 and caspase-320. Both extrinsic and intrinsic pathways are involved in TRAIL induced apoptosis. TRAIL binds to the death receptors TRAILR1 (DR4) and TRAILR2 (DR5), initiating the extrinsic pathway to activate caspase-8 and caspase-3, leading to cell death.
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