PC-1/PrLZ confers resistance to rapamycin in prostate cancer cells through increased 4E-BP1 stability

// Lan Yu 1, * , Zeng-Fu Shang 2, * , Jian Wang 1 , Hongtao Wang 3 , Fang Huang 1 , Zhe Zhang 1 , Ying Wang 1 , Jianguang Zhou 1 , Shanhu Li 1 1 Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China 2 School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu 215123, PR China 3 State Key Laboratory of Experimental Hematology Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300200, PR China * These authors have contributed equally to this work Correspondence to: Shanhu Li, e-mail: lishanhu6@163.com Jianguang Zhou, e-mail: zhou.jianguang@aliyun.com Keywords: PC-1/PrLZ, PCa, rapamycin-resistance, mTOR pathway, 4E-BP1 Received: November 28, 2014      Accepted: April 29, 2015      Published: May 11, 2015 An important strategy for improving advanced PCa treatment is targeted therapies combined with chemotherapy. PC-1 , a prostate Leucine Zipper gene (PrLZ), is specifically expressed in prostate tissue as an androgen-induced gene and is up-regulated in advanced PCa. Recent work confirmed that PC-1 expression promotes PCa growth and androgen-independent progression. However, how this occurs and whether this can be used as a biomarker is uncertain. Here, we report that PC-1 overexpression confers PCa cells resistance to rapamycin treatment by antagonizing rapamycin-induced cytostasis and autophagy (rapamycin-sensitivity was observed in PC-1-deficient (shPC-1) C4-2 cells). Analysis of the mTOR pathway in PCa cells with PC-1 overexpressed and depressed revealed that eukaryotic initiation factor 4E-binding protein 1(4E-BP1) was highly regulated by PC-1. Immunohistochemistry assays indicated that 4E-BP1 up-regulation correlates with increased PC-1 expression in human prostate tumors and in PCa cells. Furthermore, PC-1 interacts directly with 4E-BP1 and stabilizes 4E-BP1 protein via inhibition of its ubiquitination and proteasomal degradation. Thus, PC-1 is a novel regulator of 4E-BP1 and our work suggests a potential mechanism through which PC-1 enhances PCa cell survival and malignant progression and increases chemoresistance. Thus, the PC-1-4E-BP1 interaction may represent a therapeutic target for treating advanced PCa.