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, Shanhu Li

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)20356-20369
Number of pages14
JournalOncotarget
Volume6
Issue number24
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • 4E-BP1
  • MTOR pathway
  • PC-1/PrLZ
  • PCa
  • Rapamycin-resistance

ASJC Scopus subject areas

  • Oncology

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