Abstract
The mechanisms responsible for the switch of prostate cancer from androgen-sensitive (AS) to androgen-insensitive (AI) form are not well understood. Regulation of androgen receptor (AR), through which androgens control the expression of genes involved in prostate cells proliferation, migration and death also involves its cross-talk with the other signaling pathways, transcription factors and coregulatory proteins, such as β-catenin. With the aim to determine their possible contribution in triggering the switch from AS to AI form, which occurs upon androgen deprivation therapy - AR, Akt and β-catenin expression were knocked-down with respective siRNAs. Treatment of LNCaP prostate cells with siRNA for AR significantly reduced their proliferation (45-70%), expression of nuclear β- catenin, cyclin-D1, cyclin-G1, c-Myc as well as activity of metalloproteinases (MMPs) -2,-7,-9 and cell migration. Surprisingly, after longer (over 72 hrs) silencing of AR in LNCaP cells, elevated levels of p-Akt were detected and enhanced proliferation as well as expression of nuclear β-catenin, cyclin-D1, c-Myc and activity of MMPs were observed. Such effects were not observed in either PC-3 or DU145 AI cells. However, silencing of Akt and /or β-catenin in those as well as in LNCaP cells led to their decreased proliferation and migration. Our findings suggest that in prostate cancer cells, either AR or Akt signaling prevails, depending on their initial androgen sensitivity and its availability. In AI prostate cancer cells, Akt takes over the role of AR and more effectively contributes through the same signaling molecule, β-catenin, to AI cancer progression.
Highlights
Prostatic adenocarcinoma is one of the most frequently diagnosed malignancies and the second leading cause of cancer death amongst men in the developed world [1]
Prostate cancer patients are often treated based on a unique characteristic of prostatic tissue, in that it is expressly dependent on androgen whose biological effects are mediated through the androgen receptor (AR), which regulates target gene transcription with respect to its development, growth, and survival [2, 3]
To assess the actual changes in expression of AR, Akt, catenin, E- and N- cadherins, cyclin-D1, c-Myc, as well as activity of Myc as well as activity of metalloproteinases (MMPs) and cell cycle inhibitors p21Cip-1 and p27Kip-1, we used established prostate cancer cell lines: LNCaP, PC-3 and DU145, as well as primary cells derived from tissue specimens, one prostate cancer (CA-K) and one benign prostate hyperplasia line (BPH-K) [9] and respective tissues of their origin
Summary
Prostatic adenocarcinoma is one of the most frequently diagnosed malignancies and the second leading cause of cancer death amongst men in the developed world [1]. Invasive or even micrometastatic disease presents a clinical challenge, as these tumors respond poorly to standard cytotoxic regimens that act through genomic insult. Prostate cancer patients are often treated based on a unique characteristic of prostatic tissue, in that it is expressly dependent on androgen whose biological effects are mediated through the androgen receptor (AR), which regulates target gene transcription with respect to its development, growth, and survival [2, 3]. All prostate cancer patients respond well when first treated with androgen ablation. Resistance to hormonal blockade results in the recurrence of highly aggressive and metastatic prostate cancer that is androgen-independent
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