Research Papers:

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

Lan yu, Zeng-Fu Shang, Jian Wang, Hongtao Wang, Fang Huang, Zhe Zhang, Ying Wang, Jianguang Zhou and Shanhu Li _

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Oncotarget. 2015; 6:20356-20369. https://doi.org/10.18632/oncotarget.3931

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Lan Yu1,*, Zeng-Fu Shang2,*, Jian Wang1, Hongtao Wang3, Fang Huang1, Zhe Zhang1, Ying Wang1, Jianguang Zhou1, Shanhu Li1

1Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China

2School 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

3State 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: [email protected]

Jianguang Zhou, e-mail: [email protected]

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.

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