Background: Cancer stem cells (CSCs) of NPC exhibit higher tumorigenesis and metastatic potential. Novel therapies based on molecular targets of CSCs have become the focus to cure NPC. GANT61, a GLI1 inhibitor, has been reported to exhibit potent anticancer effect on many cancers; here, we evaluated whether GANT61 has inhibitory effects on NPC-CSCs and further explored the possible mechanism.

Methods: Condition medium was used to enrich NPC stem-like cells. The NPC stem-like cells characteristics were examined by Q-RT-PCR, Western blotting, MTT, BudU, colony formation, sphere formation, and subcutaneous and metastatic xenograft models. Genetic, pharmacological and biochemical approaches were applied in NPC stem-like cells to investigate molecular signals, to assess the efficacies under the inhibitors treatment, and to examine the correlation among the molecules in vitro, in vivo and NPC specimens.

Results: In the present study, we had demonstrated that NPC tumorsphere cells (NPC-TCs) possess CSC properties. The proliferation, colony formation, spheroid formation, migration, and invasion of NPC-TCs were dramatic prevented in the presence of GANT61 in vitro and in vivo. ChIP reveals that Gli1 preferentially binds to the Fibulin-5 promoter, and Fibulin-5 transcriptional/post-transcriptional levels in NPC-TCs were regulated upon GANT61 treatment. However, ectopic expression of Fibulin-5 in NPC-TCs not only enhanced self-renewal and ALDH1 expression, but also reduced the effects of GANT61-eilicted anti-tumor in vitro and in vivo. We further identified that a novel signaling, prorenin receptor/BMI1 pathway was modulated by Fibulin-5 and involved in Fibulin-5-raised self-renewal capacity of NPC-TCs in vitro and in vivo. Notably, GANT61 inhibited NPC-TCs phenotypes was associated with suppression of Fibulin-5/prorenin receptor/BMI1 signaling. Finally, a significant correlation was observed among GLI1, Fibulin-5, AT1R and BMI1 in the specimens of NPC.

Conclusions: Our data highlight that Fibulin-5/prorenin receptor/BMI1 signaling has critical role in maintaining stem-like properties of NPC-CSCs and can be efficiently targeted by GANT61 representing a preclinical therapeutic strategy to repress NPC-CSCs.

Note: This abstract was not presented at the meeting.

Citation Format: Hsin-Ting Tasi, Chang-Han Chen. GANT61-mediated constraint of Fibulin-5/prorenin receptor/BMI1 signaling impacts nasopharyngeal carcinoma stemness and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2880. doi:10.1158/1538-7445.AM2017-2880