The Activation of PI3K/AKT/mTOR Signaling Pathway  in Response to Cabazitaxel Treatment in Metastatic  Castration-Resistant Prostate Cancer Cells

Docetaxel is a first-line chemotherapy for the treatment of patients with castration-resistant prostate cancer (CRPC). Despite the good initial response of docetaxel, drug resistance will inevitably occur. Mechanisms underlying docetaxel resistance are not well elaborated. Endothelial cells (ECs) have been implicated in the progression and metastasis of prostate cancer. However, little attention has been paid to the role of endothelial cells in the development of docetaxel resistance in prostate cancer. Here, we sought to investigate the function and mechanism of endothelial cells involving in the docetaxel resistance of prostate cancer. We found that endothelial cells significantly promoted the proliferation of prostate cancer cells and decreased their sensitivity to docetaxel. Mechanistically, basic fibroblast growth factor (FGF2) secreted by endothelial cells leads to the upregulation of ETS related gene (ERG) expression and activation of the Akt/mTOR signaling pathway in prostate cancer cells to promote docetaxel resistance. In summary, these findings demonstrate a microenvironment-dependent mechanism mediating chemoresistance of prostate cancer and suggest that targeting FGF/FGFR signaling might represent a promising therapeutic strategy to overcome docetaxel resistance.

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Cotargeting Androgen Receptor Splice Variants and mTOR Signaling Pathway for the Treatment of Castration-Resistant Prostate Cancer

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-15-2119 ◽

2015 ◽

Vol 22 (11) ◽

pp. 2744-2754 ◽

Cited By ~ 30

Author(s):

Minoru Kato ◽

Carmen A. Banuelos ◽

Yusuke Imamura ◽

Jacky K. Leung ◽

Daniel P. Caley ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Signaling Pathway ◽

Splice Variants ◽

Mtor Signaling ◽

Castration Resistant Prostate Cancer ◽

Mtor Signaling Pathway ◽

Castration Resistant ◽

Androgen Receptor Splice Variants

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MicroRNA-381 facilitates autophagy and apoptosis in prostate cancer cells via inhibiting the RELN-mediated PI3K/AKT/mTOR signaling pathway

Life Sciences ◽

10.1016/j.lfs.2020.117672 ◽

2020 ◽

Vol 254 ◽

pp. 117672 ◽

Cited By ~ 2

Author(s):

Wenbiao Liao ◽

Yi Zhang

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Prostate Cancer Cells

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Dietary flavonoid tangeretin induces reprogramming of epithelial to mesenchymal transition in prostate cancer cells by targeting the PI3K/Akt/mTOR signaling pathway

Oncology Letters ◽

10.3892/ol.2017.7307 ◽

2017 ◽

Cited By ~ 3

Author(s):

Wen‑Bin Zhu ◽

Ning Xiao ◽

Xing‑Jie Liu

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Epithelial To Mesenchymal Transition ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Prostate Cancer Cells ◽

Mesenchymal Transition ◽

Dietary Flavonoid

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Statin inhibits the proliferation of human castration-resistant prostate cancer cells by controlling NFkB-LIN28B-let7 miRNA signaling pathway.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.269 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 269-269 ◽

Cited By ~ 1

Author(s):

Chang Wook Jeong ◽

Ja Hyeon Ku ◽

Hyeon Hoe Kim ◽

Cheol Kwak ◽

Minyong Kang

Keyword(s):

Prostate Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Signaling Pathway ◽

Molecular Mechanism ◽

Cell Lines ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Simvastatin Treatment ◽

Castration Resistant

269 Background: Although statin use has been associated with improved outcomes in prostate cancer, the molecular mechanism of this action is still unclear. Based on previous findings, we aimed to investigate the potential role of NFkB-Lin28B-let7 miRNA signaling pathway in human prostate cancer, particularly, castration-resistant prostate cancer (CRPC) cells, as a molecular mechanism of statin effect. Methods: Various human CRPC cell lines (PC3, DU145, 22Rv1, C42B) were used in this study. Proliferation of prostate cancer cells were measured by MTT assay and colony formation assay. Lin28B and NF-κB expression were controlled by siRNA transfection and the expression on Lin28 and let-7 miRNA were quantitated using RT-PCR and western blotting. Results: Notably, simvastatin treatment on various CRPC cell lines decreased cell viabilities in a dose dependent manner. It also significantly inhibited cell growth in clonogenic assay. In these CRPC cells, LIN28 gene was highly expressed in mRNa and protein levels. Conversely, micro RNA (miRNA) expressions of let7 family were remarkably downregulated in CRPC cells. By simvastatin treatment, mRNA and protein level of Lin28B were decreased, while let7 miRNA expressions were restored, which was the key finding of the current study. Considering NFkB is the upstream molecule of Lin28B, we found that the double treatment of statin and NF-κB inhibitor (CAPE) resulted in decreased cell viability, Lin28B and cyclin D1 expression, synergistically. Of note, let-7 miRNA levels were restored after simvastatin treatment, and further increased their expression levels by CAPE double treatment. In order to confirm this mechanistic clue, we specifically inhibited Lin28B and NF-κB genes, respectively, resulting in increased cell apoptosis signaling in the Lin28b or NF-κB knock down cells by combined treatment with simvastatin. Conclusions: In conclusion, simvastatin inhibited the cell growth of various human CRPC cell lines by controlling NFkB-LIN28B-let7 miRNA signaling pathway, and therefore; concurrent NF-κB inhibition with simvastatin treatment induce the synergistic anti-cancer effects in human CRPC cells.

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Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer

Molecular and Cellular Biology ◽

10.1128/mcb.00825-15 ◽

2015 ◽

Vol 35 (24) ◽

pp. 4185-4198 ◽

Cited By ~ 14

Author(s):

Jie Li ◽

Anju Karki ◽

Kurt B. Hodges ◽

Nihal Ahmad ◽

Amina Zoubeidi ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Glycogen Synthase ◽

Therapeutic Option ◽

Negative Regulator ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Castration Resistant

The Wnt/β-catenin signaling pathway has been identified as one of the predominantly upregulated pathways in castration-resistant prostate cancer (CRPC). However, whether targeting the β-catenin pathway will prove effective as a CRPC treatment remains unknown. Polo-like kinase 1 (Plk1) is a critical regulator in many cell cycle events, and its level is significantly elevated upon castration of mice carrying xenograft prostate tumors. Indeed, inhibition of Plk1 has been shown to inhibit tumor growth in severalin vivostudies. Here, we show that Plk1 is a negative regulator of Wnt/β-catenin signaling. Plk1 inhibition or depletion enhances the level of cytosolic and nuclear β-catenin in human prostate cancer cells. Furthermore, inhibition of Wnt/β-catenin signaling significantly potentiates the antineoplastic activity of the Plk1 inhibitor BI2536 in both cultured prostate cancer cells and CRPC xenograft tumors. Mechanistically, axin2, a negative regulator of the β-catenin pathway, serves as a substrate of Plk1, and Plk1 phosphorylation of axin2 facilitates the degradation of β-catenin by enhancing binding between glycogen synthase kinase 3β (GSK3β) and β-catenin. Plk1-phosphorylated axin2 also exhibits resistance to Cdc20-mediated degradation. Overall, this study identifies a novel Plk1-Wnt signaling axis in prostate cancer, offering a promising new therapeutic option to treat CRPC.

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