Major cause of cancer death is its metastasis to the vital organs. Few effective therapies are available for metastatic castration-resistant prostate cancer (PCa), and progressive metastatic lesions such as lymph nodes and bones cause mortality. We recently identified AES as a metastasis suppressor for colon cancer. Here, we have studied the roles of AES in PCa progression. We analyzed the relationship between AES expression and PCa stages of progression by immunohistochemistry of human needle biopsy samples. We then performed overexpression and knockdown of AES in human PCa cell lines LNCaP, DU145 and PC3, and determined the effects on proliferation, invasion and metastasis in culture and in a xenograft model. We also compared the PCa phenotypes of Aes/Pten compound knockout mice with those of Pten simple knockout mice. Expression levels of AES were inversely correlated with clinical stages of human PCa. Exogenous expression of AES suppressed the growth of LNCaP cells, whereas the AES knockdown promoted it. We also found that AES suppressed transcriptional activities of androgen receptor and Notch signaling. Notably, AES overexpression in AR-defective DU145 and PC3 cells reduced invasion and metastasis to lymph nodes and bones without affecting proliferation in culture. Consistently, prostate epithelium-specific inactivation of Aes in Pten(flox/flox) mice increased expression of Snail and MMP9, and accelerated growth, invasion and lymph node metastasis of the mouse prostate tumor. These results suggest that AES plays an important role in controlling tumor growth and metastasis of PCa by regulating both AR and Notch signaling pathways. This article is protected by copyright. All rights reserved.
Cancer science. 2017 Feb 08 [Epub ahead of print]
Yoshiyuki Okada, Masahiro Sonoshita, Fumihiko Kakizaki, Naoki Aoyama, Yoshiro Itatani, Masayuki Uegaki, Hiromasa Sakamoto, Takashi Kobayashi, Takahiro Inoue, Tomomi Kamba, Akira Suzuki, Osamu Ogawa, M Mark Taketo
Departments of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan., Departments of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan., Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.