Abstract
Wnt/β-catenin signaling is responsible for the generation of cancer stem cells (CSCs) in many human tumors, including nasopharyngeal carcinoma (NPC). Recent studies demonstrate that Wnt or PORCN inhibitor, Wnt-C59, inhibits tumor growth in MMTV-WNT1 transgenic mice. The effect of Wnt-C59 in human tumors is not clear. In this study, the NPC cell lines investigated manifest heterogeneous responses to Wnt-C59 treatment. Wnt-C59 decreased tumor growth of SUNE1 cells in mice immediately following the administration of Wnt-C59. Mice injected with HNE1 cells did not develop visible tumors after the treatment of Wnt-C59, while control mice developed 100% tumors. Wnt-C59 inhibited stemness properties of NPC cells in a dosage-dependent manner by arresting sphere formation in both HNE1 and SUNE1 cells. Thus, Wnt-C59 has the potential to eradicate CSCs in human tumors. Active β-catenin and Axin2 proteins were strongly expressed in stromal cells surrounding growing tumors, confirming the importance of Wnt signaling activities in the microenvironment being driving forces for cell growth. These novel findings confirm the ability of Wnt-C59 to suppress Wnt-driven undifferentiated cell growth in NPC. Both anti-Wnt signaling and anti-CSC approaches are feasible strategies in cancer therapy.
Highlights
The central concept of cancer stem cells (CSCs) is that the bulk of tumor cells contain a tiny cell population having self-renewal ability to sustain the long-term tumor proliferation against chemotherapy
These experiments were performed in MMTV-WNT1 transgenic mice and findings indicate that mammalian physiological Wnt signaling is sensitive to PORCN expression levels
Using several nasopharyngeal carcinoma (NPC) cell lines, we demonstrate that a PORCN inhibitor is able to inhibit Wnt signaling activities, arrest stemness properties, and suppress tumor cell growth in animal assays
Summary
The central concept of cancer stem cells (CSCs) is that the bulk of tumor cells contain a tiny cell population having self-renewal ability to sustain the long-term tumor proliferation against chemotherapy. A growing number of studies indicate that inappropriate activation of Wnt/β-catenin signaling correlates with the generation of CSCs in many tumor types [3,4,5,6,7,8] Targeting of this pathway may provide the means to safely eradicate CSCs and identify novel molecular targets for cancer therapy [9, 10]. Several recent studies provide evidence showing that PORCN inhibitors, including Wnt-C59 and LGK974, inhibit or delay tumor growth in mouse models. These experiments were performed in MMTV-WNT1 transgenic mice and findings indicate that mammalian physiological Wnt signaling is sensitive to PORCN expression levels. Wnt-C59 and LGK974 are safe agents as verified in these animal studies and the latter is in the phase I clinical trials [20, 23]
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