Figure 6. IL-8/CXCR1 signaling in CSCs treated with chemotherapy alone or in combination with repertaxin.

(A) Potential IL-8/CXCR1 cell signaling in CSCs. CXCR1 activation upon IL-8 binding induces FAK phosphorylation. Active FAK phosphorylates AKT and activates the WNT pathway, which regulates stem cell self-renewal and FOXO3A that regulates cell survival. Activation of FAK protects CSCs from a FASL/FAS-mediated bystander effect by inhibiting FADD, a downstream effector of FAS signaling. In the presence of chemotherapy, only the bulk tumor cells are sensitive to the treatment and release a high level of IL-8 and FASL proteins during the apoptotic process. Breast CSCs are stimulated via an IL-8–mediated bystander effect and are resistant to the bystander killing effect mediated by FASL. TCF, T cell factor. (B) Repertaxin treatment blocks IL-8/CXCR1 signaling and inhibits breast CSC self-renewal and survival. When repertaxin treatment is combined with chemotherapy, the CSCs are sensitized to the bystander killing effect mediated by FASL.