Int J Biol Sci 2020; 16(4):682-693. doi:10.7150/ijbs.37592

Research Paper

NVP-BEZ235 inhibits thyroid cancer growth by p53- dependent/independent p21 upregulation

Banjun Ruan1,#, Wei Liu1,#, Pu Chen1, Rongrong Cui1, Yu Li1, Meiju Ji2, Peng Hou1,3,✉, Qi Yang1,3,✉

1. Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
2. Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
3. Key Laboratory for Tumor Precision Medicine of Shaanxi Province, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China
#Contributed equally

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Citation:
Ruan B, Liu W, Chen P, Cui R, Li Y, Ji M, Hou P, Yang Q. NVP-BEZ235 inhibits thyroid cancer growth by p53- dependent/independent p21 upregulation. Int J Biol Sci 2020; 16(4):682-693. doi:10.7150/ijbs.37592. Available from http://www.ijbs.com/v16p0682.htm

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Abstract

NVP-BEZ235 is a novel dual PI3K/mTOR inhibitor, currently in phase 1/2 clinical trials, exhibiting clinical efficiency in treatment of numerous malignancies including thyroid cancer. Cancer cells harboring mutant p53 was widely reported to be blunt to pharmaceutical therapies. However, whether this genotype dependent effect also presents in thyroid cancer when treated with NVP-BEZ235 remains unknown. Therefore, in this study, the tumor suppressing effects of NVP-BEZ235 in thyroid cancer cell lines and in-vivo xenograft mouse model harboring different p53 status were examined. The antitumor effects were confirmed in p53 mutant thyroid cancer cells, though less prominent than p53 wild type cells. And for the p53 mutant cells, p53-independent upregulation of p21 plays a critical role in their response to NVP-BEZ235. Moreover, GSK3β/β-catenin signaling inhibition was implicated in the p21-mediated G0/G1 cell cycle arrest in both p53 wild type and mutant thyroid cancer cells treated with NVP-BEZ235.

Keywords: NVP-BEZ235, Thyroid cancer, PI3K/Akt/mTOR, p53, Cell cycle arrest, p21