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.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of cancerrelated deaths in men in Europe and the US [1]
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway has a prominent role in the progression of PCa and is a target therapy of advanced PCa [19]
To confirm the role of PC-1 in the regulation of eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1), we examined whether PC-1 interacted directly with 4E-binding protein 1 (4E-BP1) using glutathione S-transferase (GST) pull-down assays with recombinant GST-PC-1 and His-4E-BP1 (Fig. 4B) or GST-4E-BP1 and cell lysates transfected with Flag-PC-1 (Fig. 4C)
Summary
Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of cancerrelated deaths in men in Europe and the US [1]. Despite improvements in early screening and treatment, PCa is diagnosed in 240,000 men and causes 30,000 deaths per year in the US [2]. PTEN, a tumor suppressor protein, is often mutated or deleted in advanced PCa, activating the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway which is associated with PCa development and progression [4]. This pathway may be a molecular target for PCa treatment
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