Luteolin attenuates Wnt signaling via upregulation of FZD6 to suppress prostate cancer stemness revealed by comparative proteomics

Kun Han,Zhiqi Zhang,Yi Zhang,Tingyuan Lang,Zan Shen,Daliu Min,Lei Zhou,Roger W Beuerman,Yongning Sun

doi:10.1038/s41598-018-26761-2

Abstract

The mechanisms underlying luteolin-induced inhibition of prostate cancer (PCa) stemness have remained elusive. Here, we report that luteolin suppresses PCa stemness through Wnt signaling by upregulation of FZD6 (frizzled class receptor 6). Luteolin inhibits PCa cell proliferation, migration, self-renewal as well as the expression of prostate cancer stem cell markers in vitro. Through iTRAQ-based quantitative proteomics study, we identified 208 differentially expressed proteins in luteolin-treated PC-3 cells. Subsequent mechanistic analysis revealed that luteolin inhibits Wnt signaling by transcriptional upregulation of FZD6, and thereby suppressing the stemness of PCa cells. Furthermore, we identified FZD6 as a tumor suppressor that can abolish PCa stemness. In summary, our findings demonstrate that suppression of Wnt signaling by upregulation of FZD6 is a mechanism underlying luteolin-induced inhibition of PCa stemness. Our work suggests a new therapeutic strategy against human prostate cancer caused by aberrant activation of Wnt signaling.

Highlights

Prostate cancer (PCa) is the second leading cause of cancer death among men in the western countries[1]
We found that 48 h treatment with 5 μM of luteolin significantly inhibited the proliferation of PC-3 cells (Fig. 1B) and 18 days treatment suppressed the clonogenicity of the cells (Fig. 1C), which suggested that the maximal nontoxic dose of luteolin leads to molecular alterations involved in proliferation
We investigated whether the maximal non-toxic dose of luteolin inhibits the stemness of prostate cancer (PCa) cells

Summary

Introduction

Prostate cancer (PCa) is the second leading cause of cancer death among men in the western countries[1]. Accumulating evidence implied that cancer stem cells (CSCs) play a critical role in CRPC development and metastasis of prostate cancer[4,5,6]. Chemotherapy drugs and other novel drugs used for prostate cancer, such as enzalutamide and abiraterone, are aggressive and all have adverse side effects[9]; natural compounds, which inhibit CSCs may prove to be promising agents for prostate cancer therapy[10]. In order to enhance the understanding of the molecular mechanisms of luteolin treatment, in this study, we investigated the effects of luteolin on the proteomic profile of prostate cancer cells. We showed that a negative regulator of β-catenin transcriptional activity, FZD6 (frizzled class receptor 6), is one of the key regulators related to luteolin treatment; it inhibits Wnt signaling pathway and the stemness of prostate cancer cells. Our findings may aid improvement of translational application of luteolin and development of novel anti-prostate cancer drugs

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Results

Conclusion