CD95 and CD95L promote and protect cancer stem cells

Abstract

CD95 (APO-1/Fas) is a death receptor used by immune cells to kill cancer cells through induction of apoptosis. However, the elimination of CD95 or its ligand, CD95L, from cancer cells results in death induced by CD95R/L elimination (DICE), a type of cell death that resembles a necrotic form of mitotic catastrophe suggesting that CD95 protects cancer cells from cell death. We now report that stimulation of CD95 on cancer cells or reducing miR-200c levels increases the number of cancer stem cells (CSCs), which are more sensitive to induction of DICE than non-CSC, while becoming less sensitive to CD95 mediated apoptosis. In contrast, induction of DICE or overexpression of miR-200c reduces the number of cancer stem cells. We demonstrate that CSCs and non-CSCs have differential sensitivities to CD95-mediated apoptosis and DICE and that killing of cancer cells can be maximized by concomitant induction of both cell death mechanisms.

CD95 Signaling Inhibits B Cell Receptor-Mediated Gammaherpesvirus Replication in Apoptosis-Resistant B Lymphoma Cells

“…However, this subpopulation of cells was still susceptible to etoposideinduced cell death caused by DNA strand breaks (47) and staurosporine-induced cell death caused by activating caspase 3 (48), suggesting that the surviving cells retain intact cell death pathways mediated by other stimuli. Our observation is consistent with a recent report that constant stimulation by CD95 of breast cancer, colon cancer, and renal cancer cells leads to a subpopulation of cells less sensitive to CD95-mediated apoptosis (20). When we performed a phenotypic analysis of the apoptosis-resistant SL-1 B lymphoma cells after prolonged anti-CD95 stimulation, we did not observe any phenotypic cell surface change, which is different from the recent finding that stimulation by CD95 can transform cancer cells into a more dedifferentiated state and converts apoptosis-resistant noncancer stem cells phenotypically into cancer stem cells (20).…”

“…Our observation is consistent with a recent report that constant stimulation by CD95 of breast cancer, colon cancer, and renal cancer cells leads to a subpopulation of cells less sensitive to CD95-mediated apoptosis (20). When we performed a phenotypic analysis of the apoptosis-resistant SL-1 B lymphoma cells after prolonged anti-CD95 stimulation, we did not observe any phenotypic cell surface change, which is different from the recent finding that stimulation by CD95 can transform cancer cells into a more dedifferentiated state and converts apoptosis-resistant noncancer stem cells phenotypically into cancer stem cells (20). Thus, the mechanism underlying apoptosis resistance of SL-1 B lymphoma cells would be the other mode of regulation.…”

“…This phenomenon has led to extensive investigation into CD95 nonapoptotic function over the last several decades. Growing evidence demonstrates that the CD95-mediated nonapoptotic signal has evolved diverse roles, such as inducing activation and the proliferation of various cells (11)(12)(13)(14), increasing cancer cell motility and invasiveness (15), and promoting tumor growth and epithelial-to-mesenchymal transition, as well as promoting cancer stem cell survival (16)(17)(18)(19)(20). Additionally, activation of CD95 also triggers the secretion of inflammatory cytokines and plays an important role in inflammation (21-24).…”

“…2F), implying that resistance to CD95-mediated cell death is specific for the surviving SL-1/R cells after prolonged culture with anti-CD95 agonist. in sensitivity to CD95-mediated apoptosis (20), which prompted us to analyze whether stimulation by anti-CD95 agonist could induce any phenotypic change of SL-1/R cells. We analyzed various B cell surface markers through flow cytometry analyses.…”

New Advances and Challenges of Targeting Cancer Stem Cells

“…A long noncoding RNA suppresses miR-34a by recruiting DNA methyl-transferase Dnmt3a via prohibitin-2 and histone deacetylase 1 (161). Dr. Marcus E. Peter (Northwestern University, Chicago, IL) reported that chronic stimulation of CD95 results in lower levels of miR-200c, monitored using a sensor plasmid for miR-200c, increasing the CD24 low stem-like population in breast cancer cells (22). This is driven by a type I interferon/STAT1 pathway (23).…”