Rottlerin as a novel chemotherapy agent for adrenocortical carcinoma

Yi Zhu,Lei Zhang,Weilie Hu,Yigao Wu,Xu Zhao,Minjie Wang,Bangqi Wang

doi:10.18632/oncotarget.15221

Abstract

Adrenocortical carcinoma (ACC) is a rare, but aggressive endocrine malignancy with a generally poor clinical outcome. There is no effective therapy for advanced and metastatic ACC. In our study, we found that an existing drug (rottlerin) exerted its tumour-suppressive function in ACC. Specifically, rottlerin inhibited cellular proliferation of ACC cell lines (NCI-H295R and SW-13) in a dose- and time-dependent manner. We also found that rottlerin induced cell apoptosis and promoted G0/G1 cell cycle arrest in ACC cell lines. The cellular migration and invasion of ACC cell lines were decreased after treatment with rottlerin. Further, the molecular expression of lipoprotein receptor related protein 6 (LRP6) and β-catenin were down-regulated in rottlerin-treated ACC cells, which indicated that Wnt/β-catenin signaling was involved in the tumour-suppressive function of rottlerin. To further confirm the anti-tumour function of rottlerin, a nude mouse ACC xenograft model was used. The xenograft growth curves and TUNEL assays demonstrated that rottlerin inhibited proliferation and induced apoptosis in the ACC xenograft model. Furthermore, we verified that rottlerin down-regulated the expression of LRP6 and β-catenin in vivo. The ACC cell line and xenograft mouse model data indicated that rottlerin significantly inhibited proliferation and induced apoptosis of ACC cells, likely via suppression of the Wnt/β-catenin signaling pathway. Our study indicated the potential therapeutic utility of rottlerin as a novel and potential chemotherapeutic agent for ACC.

Highlights

Adrenocortical carcinoma (ACC) is a rare, but typically aggressive malignancy with an estimated annual incidence of 0.7–2.0 cases per million population
The molecular expression of lipoprotein receptor related protein 6 (LRP6) and β-catenin were down-regulated in rottlerin-treated ACC cells, which indicated that Wnt/β-catenin signaling was involved in the tumour-suppressive function of rottlerin
We performed H&E (Figure 4D) and immunohistochemistry staining in xenograft tissues, and the results showed that rottlerin down-regulated the expression of β-catenin, LRP6, and p-LRP compared with the control and dimethyl www.impactjournals.com/oncotarget sulfoxide (DMSO)-treated groups in vivo (Figure 5, *p < 0.05)

Summary

Introduction

Adrenocortical carcinoma (ACC) is a rare, but typically aggressive malignancy with an estimated annual incidence of 0.7–2.0 cases per million population. ACCs are highly aggressive with a poor prognosis and an overall survival rate at 5 years of only 25%–50% in most series [1, 2]. Radical surgical resection has been the only potentially curative option for ACC; approximately 40% of patients initially present with distant metastases. Even after seemingly complete removal of the tumor, recurrences occur in approximately 60%–80% of ACC patients [3]. There is no effective therapy for patients with advanced or recurrent. The combination of a cytotoxic drug and mitotane is recommended as first-line therapy in advanced ACCs, but the poor therapeutic efficiency (< 40%) and severe side effects limits clinical utility [4].

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Results

Conclusion