Dual Targeting of the Akt/mTOR Signaling Pathway Inhibits Castration-Resistant Prostate Cancer in a Genetically Engineered Mouse Model

Abstract Background 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 (PCa). However, little attention has been paid to the role of ECs in the development of docetaxel resistance in PCa. Methods Here, we sought to investigate the function and mechanism of ECs involving in the docetaxel resistance of PCa. The 22Rv1 and C4-2B PCa cell lines were cultured with or without human umbilical vein endothelial cells (HUVEC). The proliferation of each PCa cell line was assessed by CCK8 and EdU assays. Cell viability of each PCa cell line treated with docetaxel was evaluated by CCK8. Apoptosis was measured by flow cytometry. Quantitative reverse transcription (RT)-PCR assay was used to determine the expression of ETS related gene (ERG) in each PCa cell line and FGF2 in HUVEC. The proteins including ERG, Caspase3, PARP, Akt, p-Akt, mTOR and p-mTOR were quantified by western blotting. ERG overexpressing C4-2B cells(C4-2B-ERG) were constructed by transfection with pLenti6.3-ERG lentivirus. C4-2B-ERG cells were knocked down by transfecting with ERG siRNAs. Differentially expressed cytokines between the serum-free media from 22Rv1 and 22Rv1/HUVEC co-culture system were detected by human cytokine array and determined by ELISA assay. Tumors were induced in mice by injecting 22Rv1 cells with or without HUVEC and treated with docetaxel. Tumor growth and apoptosis were examined by immunohistochemistry and TUNEL respectively. Results ECs promoted proliferation and inhibited apoptosis in PCa cells (in vitro) and mouse xenograft tumors induced by these cells (in vivo) under docetaxel treatment. ECs secreted FGF2 to induce ERG expression and activate the Akt/mTOR signaling pathway in PCa cells contributing to docetaxel resistance. Blocking FGF2 could reverse the enhancing effects of HUVEC on docetaxel resistance in PCa cells. Inhibition of the Akt/mTOR signaling pathway could alleviate chemoresistance mediated by ERG. Conclusion ECs promote docetaxel resistance via FGF2/ERG/Akt/mTOR signaling pathway in PCa cells. Targeting FGF/ FGFR signaling may represent a promising therapeutic strategy to overcome docetaxel resistance.

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Endothelial Cells Promote Docetaxel Resistance of Prostate Cancer Cells by Inducing ERG Expression and Activating Akt/mTOR Signaling Pathway

Frontiers in Oncology ◽

10.3389/fonc.2020.584505 ◽

2020 ◽

Vol 10 ◽

Author(s):

Wenhao Zhou ◽

Yiming Su ◽

Yu Zhang ◽

Bangmin Han ◽

Haitao Liu ◽

...

Keyword(s):

Prostate Cancer ◽

Endothelial Cells ◽

Cancer Cells ◽

Signaling Pathway ◽

Initial Response ◽

Mtor Signaling ◽

Castration Resistant Prostate Cancer ◽

Mtor Signaling Pathway ◽

Prostate Cancer Cells ◽

Docetaxel Resistance

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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Aberrant TGF-β Signaling Drives Castration-Resistant Prostate Cancer in a Male Mouse Model of Prostate Tumorigenesis

Endocrinology ◽

10.1210/en.2017-00086 ◽

2017 ◽

Vol 158 (6) ◽

pp. 1612-1622 ◽

Cited By ~ 13

Author(s):

Hong Pu ◽

Diane E. Begemann ◽

Natasha Kyprianou

Keyword(s):

Prostate Cancer ◽

Mouse Model ◽

Male Mouse ◽

Castration Resistant Prostate Cancer ◽

Prostate Tumorigenesis ◽

Castration Resistant

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Inhibition of Prostate Cancer DU-145 Cells Proliferation by Anthopleura anjunae Oligopeptide (YVPGP) via PI3K/AKT/mTOR Signaling Pathway

Marine Drugs ◽

10.3390/md16090325 ◽

2018 ◽

Vol 16 (9) ◽

pp. 325 ◽

Cited By ~ 16

Author(s):

Xiaojuan Li ◽

Yunping Tang ◽

Fangmiao Yu ◽

Yu Sun ◽

Fangfang Huang ◽

...

Keyword(s):

Prostate Cancer ◽

Signaling Pathway ◽

Caspase 3 ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Nude Mouse Model ◽

Dose Dependent

We investigated the antitumor mechanism of Anthopleura anjunae oligopeptide (AAP-H, YVPGP) in prostate cancer DU-145 cells in vitro and in vivo. Results indicated that AAP-H was nontoxic and exhibited antitumor activities. Cell cycle analysis indicated that AAP-H may arrest DU-145 cells in the S phase. The role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/AKT/mTOR) signaling pathway in the antitumor mechanism of APP-H was investigated. Results showed that AAP-H treatment led to dose-dependent reduction in the levels of p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448), whereas t-AKT and t-PI3K levels remained unaltered compared to the untreated DU-145 cells. Inhibition of PI3K/AKT/mTOR signaling pathway in the DU-145 cells by employing inhibitor LY294002 (10 μM) or rapamycin (20 nM) effectively attenuated AAP-H-induced phosphorylation of AKT and mTOR. At the same time, inhibitor addition further elevated AAP-H-induced cleaved-caspase-3 levels. Furthermore, the effect of AAP-H on tumor growth and the role of the PI3K/AKT/mTOR signaling pathway in nude mouse model were also investigated. Immunohistochemical analysis showed that activated AKT, PI3K, and mTOR levels were reduced in DU-145 xenografts. Western blotting showed that AAP-H treatment resulted in dose-dependent reduction in p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448) levels, whereas t-AKT and t-PI3K levels remained unaltered. Similarly, Bcl-xL levels decreased, whereas that of Bax increased after AAP-H treatment. AAP-H also increased initiator (caspase 8 and 9) and executor caspase (caspase 3 and 7) levels. Therefore, the antitumor mechanism of APP-H on DU-145 cells may involve regulation of the PI3K/AKT/mTOR signaling pathway, which eventually promotes apoptosis via mitochondrial and death receptor pathways. Thus, the hydrophobic oligopeptide (YVPGP) can be developed as an adjuvant for the prevention or treatment of prostate cancer in the future.

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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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Activation of mTOR signaling pathway is secondary to neuronal excitability in a mouse model of mesio-temporal lobe epilepsy

European Journal of Neuroscience ◽

10.1111/ejn.12835 ◽

2015 ◽

Vol 41 (7) ◽

pp. 976-988 ◽

Cited By ~ 36

Author(s):

Ayako Shima ◽

Naoki Nitta ◽

Fumio Suzuki ◽

Anne-Marie Laharie ◽

Kazuhiko Nozaki ◽

...

Keyword(s):

Mouse Model ◽

Temporal Lobe Epilepsy ◽

Signaling Pathway ◽

Temporal Lobe ◽

Neuronal Excitability ◽

Mtor Signaling ◽

Mtor Signaling Pathway

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Imipramine Inhibits Migration and Invasion in Metastatic Castration-Resistant Prostate Cancer PC-3 Cells via AKT-Mediated NF-κB Signaling Pathway

Molecules ◽

10.3390/molecules25204619 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4619

Author(s):

Eun Yeong Lim ◽

Joon Park ◽

Yun Tai Kim ◽

Min Jung Kim

Keyword(s):

Prostate Cancer ◽

Protein Expression ◽

Signaling Pathway ◽

Cancer Progression ◽

Migration And Invasion ◽

Dependent Manner ◽

Castration Resistant Prostate Cancer ◽

Monocyte Chemoattractant Protein 1 ◽

Downstream Signaling ◽

Castration Resistant

Imipramine (IMI) is a tricyclic synthetic antidepressant that is used to treat chronic psychiatric disorders, including depression and neuropathic pain. IMI also has inhibitory effects against various cancer types, including prostate cancer; however, the mechanism of its anticancer activity is not well understood. In the present study, we investigated the antimetastatic and anti-invasive effects of IMI in metastatic castration-resistant prostate cancer PC-3 cells, with an emphasis on the serine/threonine protein kinase AKT-mediated nuclear factor kappa B (NF-κB) signaling pathway. While IMI did not induce cell death, it attenuated PC-3 cell proliferation. According to the wound healing assay and invasion assay, migration and invasion in PC-3 cells were significantly inhibited by IMI in a dose-dependent manner. IMI significantly downregulated p-AKT protein expression but upregulated phospho-extracellular signal-regulated kinase (ERK1)/2 protein expression levels. Furthermore, IMI treatment resulted in decreased AKT-mediated downstream signaling, including p-inhibitor of κB kinase (IKK)α/β, p-inhibitor of κB (IκBα), and p-p65. Inhibited NF-κB signaling reduced the secretion of several proinflammatory cytokines and chemokine by PC-3 cells. Overall, our study explored the negative correlation between the use of antidepressants and prostate cancer progression, showing that IMI attenuated cell viability, migration, and invasion of PC-3 cells by suppressing the expression of AKT and NF-κB-related signaling proteins and secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1).

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