Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours
-
Published:2021-03-03
Issue:9
Volume:124
Page:1566-1580
-
ISSN:0007-0920
-
Container-title:British Journal of Cancer
-
language:en
-
Short-container-title:Br J Cancer
Author:
Gampala Silpa, Shah Fenil, Zhang Chi, Rhodes Steven D., Babb Olivia, Grimard Michelle, Wireman Randall S., Rad Ellie, Calver Brian, Bai Ren-Yuan, Staedtke Verena, Hulsey Emily L., Saadatzadeh M. Reza, Pollok Karen E., Tong Yan, Smith Abbi E., Clapp D. Wade, Tee Andrew R., Kelley Mark R., Fishel Melissa L.ORCID
Abstract
Abstract
Background
MPNST is a rare soft-tissue sarcoma that can arise from patients with NF1. Existing chemotherapeutic and targeted agents have been unsuccessful in MPNST treatment, and recent findings implicate STAT3 and HIF1-α in driving MPNST. The DNA-binding and transcriptional activity of both STAT3 and HIF1-α is regulated by Redox factor-1 (Ref-1) redox function. A first-generation Ref-1 inhibitor, APX3330, is being tested in cancer clinical trials and could be applied to MPNST.
Methods
We characterised Ref-1 and p-STAT3 expression in various MPNST models. Tumour growth, as well as biomarkers of apoptosis and signalling pathways, were measured by qPCR and western blot following treatment with inhibitors of Ref-1 or STAT3.
Results
MPNSTs from Nf1-Arfflox/floxPostnCre mice exhibit significantly increased positivity of p-STAT3 and Ref-1 expression when malignant transformation occurs. Inhibition of Ref-1 or STAT3 impairs MPNST growth in vitro and in vivo and induces apoptosis. Genes highly expressed in MPNST patients are downregulated following inhibition of Ref-1 or STAT3. Several biomarkers downstream of Ref-1 or STAT3 were also downregulated following Ref-1 or STAT3 inhibition.
Conclusions
Our findings implicate a unique therapeutic approach to target important MPNST signalling nodes in sarcomas using new first-in-class small molecules for potential translation to the clinic.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
Reference41 articles.
1. Reilly, K. M., Kim, A., Blakely, J., Ferner, R. E., Gutmann, D. H., Legius, E. et al. Neurofibromatosis type 1-associated MPNST state of the science: outlining a research agenda for the future. J. Natl Cancer Inst. 109 https://doi.org/10.1093/jnci/djx124 (2017). 2. Kim, A., Stewart, D. R., Reilly, K. M., Viskochil, D., Miettinen, M. M. & Widemann, B. C. Malignant peripheral nerve sheath tumors state of the science: leveraging clinical and biological insights into effective therapies. Sarcoma 2017, 7429697 (2017). 3. Van Schaeybroeck, S., Kalimutho, M., Dunne, P. D., Carson, R., Allen, W., Jithesh, P. V. et al. ADAM17-dependent c-MET-STAT3 signaling mediates resistance to MEK inhibitors in KRAS mutant colorectal cancer. Cell Rep. 7, 1940–1955 (2014). 4. Zushi, S., Shinomura, Y., Kiyohara, T., Miyazaki, Y., Kondo, S., Sugimachi, M. et al. STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells. Int. J. Cancer 78, 326–330 (1998). 5. Rad, E., Dodd, K., Thomas, L., Upadhyaya, M. & Tee, A. STAT3 and HIF1alpha signaling drives oncogenic cellular phenotypes in malignant peripheral nerve sheath tumors. Mol. Cancer Res. 13, 1149–1160 (2015).
Cited by
9 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|