CAMK2N1 inhibits prostate cancer progression through androgen receptor-dependent signaling

Abstract

// Tao Wang 1,2 , Shuiming Guo 1,2 , Zhuo Liu 1,2 , Licheng Wu 1,2 , Mingchao Li 1,2 , Jun Yang 1,2 , Ruibao Chen 1,2 , Xiaming Liu 1,2 , Hua Xu 1,2 , Shaoxin Cai 3 , Hui Chen 6 , Weiyong Li 6 , Shaohua Xu 9 , Liang Wang 4 , Zhiquan Hu 1,2 , Qianyuan Zhuang 1,2 , Liping Wang 7 , Kongming Wu 5 , Jihong Liu 1,2 , Zhangqun Ye 1,2 , Jun-Yuan Ji 8 , Chenguang Wang 10 and Ke Chen 1,2,7 1 Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 2 Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 3 Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 4 Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 5 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 6 Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 7 Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA 8 Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX, USA 9 Department of Gynecology, Shanghai First Matenity and Infant Hospital, Tongji University School of Medicine, Shanghai, China 10 Key Laboratory of Tianjin Radiation and Molecular Nuclear Medicine; Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, China Correspondence: Ke Chen, email: // Keywords : CAMK2N1, Androgen receptor (AR), prostate cancer, tumor suppressor Received : July 10, 2014 Accepted : September 24, 2014 Published : September 25, 2014 Abstract Castration resistance is a major obstacle to hormonal therapy for prostate cancer patients. Although androgen independence of prostate cancer growth is a known contributing factor to endocrine resistance, the mechanism of androgen receptor deregulation in endocrine resistance is still poorly understood. Herein, the CAMK2N1 was shown to contribute to the human prostate cancer cell growth and survival through AR-dependent signaling. Reduced expression of CAMK2N1 was correlated to recurrence-free survival of prostate cancer patients with high levels of AR expression in their tumor. CAMK2N1 and AR signaling form an auto-regulatory negative feedback loop: CAMK2N1 expression was down-regulated by AR activation; while CAMK2N1 inhibited AR expression and transactivation through CAMKII and AKT pathways. Knockdown of CAMK2N1 in prostate cancer cells alleviated Casodex inhibition of cell growth, while re-expression of CAMK2N1 in castration-resistant cells sensitized the cells to Casodex treatment. Taken together, our findings suggest that CAMK2N1 plays a tumor suppressive role and serves as a crucial determinant of the resistance of prostate cancer to endocrine therapies.