Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression

Hangchuan Shi,Chawnshang Chang,Michiaki Hamada,Xiong Yang,Yin Sun,Tsukasa Fukunaga,Miao He,Xiaoping Zhang

doi:10.1038/s41388-019-0962-8

Abstract

Renal cell carcinoma (RCC) is one of the most lethal urological tumors. Using sunitinib to improve the survival has become the first-line therapy for metastatic RCC patients. However, the occurrence of sunitinib resistance in the clinical application has curtailed its efficacy. Here we found TR4 nuclear receptor might alter the sunitinib resistance to RCC via altering the TR4/lncTASR/AXL signaling. Mechanism dissection revealed that TR4 could modulate lncTASR (ENST00000600671.1) expression via transcriptional regulation, which might then increase AXL protein expression via enhancing the stability of AXL mRNA to increase the sunitinib resistance in RCC. Human clinical surveys also linked the expression of TR4, lncTASR, and AXL to the RCC survival, and results from multiple RCC cell lines revealed that targeting this newly identified TR4-mediated signaling with small molecules, including tretinoin, metformin, or TR4-shRNAs, all led to increase the sunitinib sensitivity to better suppress the RCC progression, and our preclinical study using the in vivo mouse model further proved tretinoin had a better synergistic effect to increase sunitinib sensitivity to suppress RCC progression. Future successful clinical trials may help in the development of a novel therapy to better suppress the RCC progression.

Highlights

These authors contributed : Hangchuan Shi, Yin Sun
As recent studies indicated that Testicular orphan receptor 4 (TR4) could impact Renal cell carcinoma (RCC) progression [21, 22], we were interested to see if hypoxia may function via altering TR4 to influence the sunitinib sensitivity
The results revealed that hypoxia could significantly increase TR4 expression in both RCC OSRC-2 and SW839 cells (Fig. 1c)

Summary

Introduction

Sunitinib will inhibit receptor tyrosine kinases in the RCC cells, and overall resistance to sunitinib likely will derive from the combined effects on vessels and on tumor cells. We will examine the molecular mechanisms of sunitinib resistance in RCC cells with a focus on the role of Testicular orphan receptor 4 (TR4) under hypoxic conditions compared with normoxic conditions. AXL signaling was found essential for VEGFmediated activation of PI3K/AKT and migration of endothelial cells, suggesting that overexpression of AXL may serve as a mechanism of resistance to anti-angiogenic therapies [13]. We demonstrate that hypoxia increases TR4, which plays a critical role in regulating RCC resistance to sunitinib through lncTASR (ENST00000600671.1) that in turn regulates AXL. We delineated a novel pathway for TR4’s effects on the sunitinib resistance as well as provide a mechanistic explanation, and more importantly, we provided potential therapeutic approaches to overcome this resistance

Results

Discussion

Methods

Compliance with ethical standards