ASC-J9 suppresses renal cell carcinoma progression by targeting an androgen receptor-dependent HIF2α/VEGF signaling pathway.

Lei Li,Chawnshang Chang,Guodong Zhu,Dalin He,Zhenfeng Guan,Shuyuan Yeh,Yuan Chen,Liang Liang,Luke Chang

doi:10.1158/0008-5472.can-13-2681

Abstract

Males have a higher incidence of renal cell carcinoma (RCC) than females, but the reason for this gender difference is unknown. Addressing this question, we report the discovery of an androgen receptor (AR)-induced HIF2α/VEGF signal that drives RCC progression. AR attenuation or augmentation in RCC cells altered their proliferation, migration, and invasion in multiple models in vitro and in vivo. Mechanistic investigations revealed that AR targeting inhibited RCC cell migration and invasion by modulating HIF2α/VEGF signals at the level of mRNA and protein expression. Interrupting HIF2α/VEGF signals with inhibitors of either HIF2α or VEGF was sufficient to suppress RCC progression. Similarly, the specific AR degradation enhancer ASC-J9 was sufficient to suppress AR-induced HIF2α/VEGF signaling and RCC progression in multiple models in vitro and in vivo. Taken together, our results revealed a novel role for AR in RCC initiation and progression with implications for novel therapeutic strategies.

Highlights

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90% to 95% of kidney neoplasm [1]
The normal human kidney epithelial cells stably transfected with androgen receptor (AR) (HKC5-AR) and vehicle Vector (HKC5-Vec) were both transformed by carcinogen Fe-NTA (10 mmol/L) for 4 weeks to form cell colonies in soft agar cell culture dishes, and results showed that HKC5-AR cells had significantly higher colony formation capabilities as compared with those of transformed HKC5-Vec cells (Fig. 1A)
We xenografted the Fe-NTA–transformed normal kidney epithelial cells (HKC5AR/HKC5-Vec) and human renal carcinoma 786O-AR/Vec RCC tumor cells into the male mice subcutaneously, and the results indicated that AR could promote both the transformed normal renal epithelial cells and the RCC cells to form bigger tumors compared to vector tumors in these in vivo mouse models (Fig. 5A and B)

Summary

Introduction

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90% to 95% of kidney neoplasm [1]. Incidence and mortality rates are reported to be steadily rising at a rate of approximately 2% to 3% per decade [2]. Surgery remains the only effective treatment for RCC because metastatic disease is usually resistant to radiotherapy and chemotherapy, and immunotherapy shows limited response rates of 15% to 20% [3]. The development of protein tyrosine kinase inhibitor therapy opens a new door for advanced RCC patients, its effect is still limited for patients with selective pathologic types [4]. The search for a new and better therapy via new targets for metastatic RCC is still needed. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/)

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Results

Conclusion