Aristolochic Acid Affects Upper Tract Urothelial Cancer Behavior through the MAPK Pathway.

Chen Chen,Su Su,Lee Lee,Lin Lin,Yu Yu,Huang Huang,Sung Sung,Luo Luo,Chiang Chiang

doi:10.3390/molecules24203707

Abstract

The prevalence of upper tract urothelial carcinoma (UTUC) in Taiwan is relatively higher than thatin Western countries. Aristolochic acid (AA), which is widely used in traditional Chinese herbology, is now recognized to be one of the carcinogens for UTUC. Numerous UTUC patients have chronic kidney diseases or end-stage renal diseases; however, little literature hasreported on theoncogenic pathway of AA-related UTUC. The aim of our study was to identify the potential target treatment for AA-related UTUC. Here, we established an AA pre-exposure followed bya 3-methylcholanthrene (MCA) stimulus tumorigenic cell model. We not only demonstrated that AA pre-exposure MCA stimulus tumorigenic cells have more behaviors of cell migration and invasion by enhancing the metalloproteinases (MMP) activity, which is compatible with clinical findings of AA-related UTUC, but we also validated that AA pre-exposure MCA stimulus tumorigeniccells could be activated through the mitogen-activated protein kinases (MAPK) pathway. We further dissected the route of the MAPK pathway and found that the p38 and extracellular signal regulated kinases (ERK) sub-pathways might play essential roles in AA pre-exposure urothelial cancer cell lines. This consequence was also corroborated with a tissue study in AA-exposed patients.

Highlights

Over the last fewdecades, the incidence of urothelialcancers, which accounted for 10% of all new malignancies in 2012, has gradually increased in Taiwan [1,2]
We established an in vitro model of the long-term exposure of cells to Aristolochic acid (AA), and we further explored the molecular mechanism associated with tumorigenic transformation
The results showed that the higher the concentration of AA, the greater the phosphorylation of p38 and extracellular signal regulated kinases (ERK), but no significant change was observed for c-jun N-terminal kinase (JNK), while the upstream of mitogen-activated protein kinases (MAPK), growth factor receptor-bound protein 2 (GRB2) and focal adhesion kinase (FAK) were increased, and MAPK phosphorylation kinases MEKK4 (MAPK kinase kinasekinase4) and mitogen-activated protein kinase kinase3 (MKK3) showed significant upward trends, indicating that AA may pass through the p38 and ERK pathways to induce

Summary

Introduction

The incidence of urothelialcancers, which accounted for 10% of all new malignancies in 2012, has gradually increased in Taiwan [1,2]. Molecules 2019, 24, 3707; doi:10.3390/molecules24203707 www.mdpi.com/journal/molecules (UTUC), arising from the urothelial lining of the urinary tract from renal calyces to the ureteral orifice, comprises only 5% of all urothelial carcinomas in Western countries [3,4,5], but it represents 31% of all urothelial carcinomas in Taiwan [6,7,8]. The high prevalence of UTUC has identified Taiwan as an endemic area [9]. AA is recognized as a human carcinogen with a high correlation with the development of UTUC. It is worthnoting that AA-induced UTUC (AA-UTUC) patients tend to be younger and have poorer renal function, contributing to difficulties in cancer treatment [13,14,15].

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