Open Access

ARTICLE

Suppression of Asparaginyl Endopeptidase Inhibits Polyomavirus Middle T Antigen-Induced Tumor Formation and Metastasis

Cheng Xu^*1, Lu Cao^*1, Jianhua Liu^†1, Zhongrun Qian^‡, Yu Peng^§, Wenjing Zhu^§, Yongming Qiu^‡, Yingying Lin^‡¶

* Department of Radiation Oncology, Ruijin Hospital, Shanghai, P.R. China
† Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
‡ Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
§ Department of Urology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
¶ Shanghai Institute of Head Trauma, Shanghai, P.R. China
1 These authors provided equal contribution to this work.

Oncology Research 2017, 25(3), 407-415. https://doi.org/10.3727/096504016X14743350548249

Abstract

Elevated circulating asparaginyl endopeptidase (AEP), a novel lysosomal protease, has been found in breast cancer, and AEP is thus considered to be a prognostic factor in this disease. However, the pathological functions of circulating AEP in the development of breast cancer and the potential of AEP-targeted therapy remain unclear. We used MMTV-PyVmT transgenic mice, which spontaneously develop mammary tumors. Western blotting showed overexpression of AEP in both primary tumor tissue and lung metastases compared to their normal counterparts. Moreover, the concentration of circulating AEP gradually increased in the serum during the development of mammary tumors. Purified AEP protein injected through the tail vein promoted tumor growth and mammary tumor metastasis and shortened survival, whereas AEP-specific small compound inhibitors (AEPIs) effectively suppressed tumor progression and prolonged host survival. Further analysis of the molecular mechanism revealed that AEP was important for PI3K/AKT pathway activation. Thus, an elevated serum AEP level was closely related to mammary cancer progression and metastasis, and AEP is a potential target for breast cancer therapy in the clinic.

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