Effect of PI3K/Akt Signaling Pathway on the Process of Prostate Cancer Metastasis to Bone

Abstract

We sought to study the effects of PI3K/Akt pathway and its downstream substrate NF-κB on prostate cancer bone metastatic process. Expression level of active p-Akt in PC3 cells was upregulated by transient expression with constitutively active plasmid CA-Akt or, alternatively, suppressed by dominant negative construct DN-Akt. NF-κB activity was determined by luciferase reporter assays. mRNA and protein expressions of receptor activator of NF-κB ligand (RANKL), parathyroid hormone-related protein (PTHrP), and bone morphogenetic protein 2 (BMP-2) were evaluated using RT-PCR and Western blotting. The effect of cross-talk between PC3 and SaOS2 cells on cell proliferation was analyzed using a co-culture system. Stimulation of p-Akt promoted NF-κB activity, and led to an increase in mRNA and protein expressions of RANKL, PTHrP, and BMP-2 in PC3 PCa cells through NF-κB. Co-culturing PC3 and SaOS2 cells significantly increased the expression of p-Akt and the activity of NF-κB, and promoted proliferation of both PC3 and SaOS2 cells. Increasing expression levels of p-Akt by transfection with CA-Akt led to further increase in cells proliferation, whereas NF-κB inhibitor PDTC partially blocked this effect. PI3K/Akt pathway stimulates the expressions of RANKL, PTHrP, and BMP-2 partly through NF-κB, suggesting its importance for bone metastasis of prostate carcinoma. Interaction of prostate cancer cells with bone cells has a stimulatory effect on cell proliferation.

Functional role and tobacco smoking effects on methylation ofCYP1A1gene in prostate cancer

“…This inhibition of AKT could then promote FOXO3a and Par-4 activation leading to apoptosis as was demonstrated in prostate cancer cells by Das et al [49]. Also in a report by Zhu et al [50], silencing of prostatic PC3 cells for AKT resulted in reductions of growth promoting RANKL , PTHrP , and BMP-2 . Taken together, our results suggest that CYP1A1 may act as an upstream activator of the PI3K-AKT signaling pathway and enhance the transcriptional activation of anti-apoptotic genes that include BCL2 ; and further studies are needed to verify this hypothesis.…”

Retracted: Knockdown of SRPX2 inhibits the proliferation, migration, and invasion of prostate cancer cells through the PI3K/Akt/mTOR signaling pathway

“…[23][24][25] The PI3K/Akt/mTOR pathway is frequently activated in advanced prostate cancer. [23][24][25] The PI3K/Akt/mTOR pathway is frequently activated in advanced prostate cancer.…”

ST6Gal-I overexpression facilitates prostate cancer progression via the PI3K/Akt/GSK-3β/β-catenin signaling pathway

“…Here, we observed that it's downstream signaling pathway, the PI3K/Akt signaling pathway was much more active in PC-3 cells. Zhu et al reported that stimulation of PI3K/Akt/NF-kappaB signaling in PC-3 cells upregulates the expression of the steoclastogenesis factors RANK and PTHrP and the osteoblastogenesis factor BMP-2, which may play roles in a variety of bone metastasis-related processes [ 46 – 48 ]. These findings indicate a possible role of ST6Gal-I in PC-3 cell bone metastasis.…”