title: PC-1/PrLZ confers resistance to rapamycin in prostate cancer cells through increased 4E-BP1 stability.
abstract: 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.
authors.affiliation: Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Zeng-Fu
authors.initials: ZF
authors.lastname: Shang
authors.affiliation: Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
authors.affiliation: Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China.
authors.forename: Jianguang
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, PR China.
authors.forename: Shanhu
authors.initials: S
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D008297:Male; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011755:Pyrophosphatases / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; D020123:Sirolimus
keywords: 4E-BP1; PC-1/PrLZ; PCa; mTOR pathway; rapamycin-resistance