title: Suppression of Asparaginyl Endopeptidase Inhibits Polyomavirus Middle T Antigen-Induced Tumor Formation and Metastasis.
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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xu
authors.forename: Lu
authors.initials: L
authors.lastname: Cao
authors.forename: Jianhua
authors.initials: J
authors.lastname: Liu
authors.forename: Zhongrun
authors.initials: Z
authors.lastname: Qian
authors.forename: Yu
authors.initials: Y
authors.lastname: Peng
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhu
authors.forename: Yongming
authors.initials: Y
authors.lastname: Qiu
authors.forename: Yingying
authors.initials: Y
authors.lastname: Lin
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D000957:Antigens, Viral, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011120:Polyomavirus / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D000099240:Asparaginyl Endopeptidase
chemical_list: D000952:Antigens, Polyomavirus Transforming; D000957:Antigens, Viral, Tumor; D003546:Cysteine Endopeptidases; D019869:Phosphatidylinositol 3-Kinases; D000099240:Asparaginyl Endopeptidase