Androgen suppresses protein kinase D1 expression through fibroblast growth factor receptor substrate 2 in prostate cancer cells.

Liyong Zhang,Q. Jane Wang,Courtney R. LaValle,Manuj Tandon,Zhenlong Zhao,Fan Deng,Shuping Xu

doi:10.18632/oncotarget.14536

Abstract

In prostate cancer, androgen/androgen receptor (AR) and their downstream targets play key roles in all stages of disease progression. The protein kinase D (PKD) family, particularly PKD1, has been implicated in prostate cancer biology. Here, we examined the cross-regulation of PKD1 by androgen signaling in prostate cancer cells. Our data showed that the transcription of PKD1 was repressed by androgen in androgen-sensitive prostate cancer cells. Steroid depletion caused up regulation of PKD1 transcript and protein, an effect that was reversed by the AR agonist R1881 in a time- and concentration-dependent manner, thus identifying PKD1 as a novel androgen-repressed gene. Kinetic analysis indicated that the repression of PKD1 by androgen required the induction of a repressor protein. Furthermore, inhibition or knockdown of AR reversed AR agonist-induced PKD1 repression, indicating that AR was required for the suppression of PKD1 expression by androgen. Downstream of AR, we identified fibroblast growth factor receptor substrate 2 (FRS2) and its downstream MEK/ERK pathway as mediators of androgen-induced PKD1 repression. In summary, PKD1 was identified as a novel androgen-suppressed gene and could be downregulated by androgen through a novel AR/FRS2/MEK/ERK pathway. The upregulation of prosurvival PKD1 by anti-androgens may contribute to therapeutic resistance in prostate cancer treatment.

Highlights

Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer-related deaths among men in the United States
PKD3 was upregulated upon androgen withdraw in LNCaP cells, despite its low endogenous expression (Supplementary Figure 1A)
Androgen did not affect the expression of PKD1 and PKD2 in another castration-resistant cell line, 22Rv1, which expresses both full-length androgen receptor (AR) and truncated AR variants (Supplementary Figure 1C), suggesting that the effect of androgen may be cell context-dependent

Summary

Introduction

Androgen deprivation therapy provides an initial favorable response in advanced prostate cancer, the more aggressive castration-resistant prostate cancer (CRPC) develops invariably in almost all patients, eventually leading to death. It has become increasingly clear that continuous activation of the AR in CRPC remains the main driving force of tumor progression and metastasis. A recent report suggested that a hotspot activating mutation in PRKD1, the gene encoding PKD1, may drive polymorphous low-grade adenocarcinoma (PLGA), the second most frequent type of malignant tumor of the minor salivary glands [14]. PKD has been shown to play an important role in the pathogenesis of prostate cancer [20, 24,25,26], and targeted PKD inhibition potently blocks prostate cancer cell proliferation and survival [26, 27]

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Results

Conclusion