Supraphysiological androgen levels induce cellular senescence in human prostate cancer cells through the Src-Akt pathway

Roediger, Julia; Hessenkemper, Wiebke; Bartsch, Sophie; Manvelyan, Marina; Huettner, Soeren S; Liehr, Thomas; Esmaeili, Mohsen; Foller, Susan; Petersen, Iver; Grimm, Marc‐Oliver; Baniahmad, Aria

doi:10.1186/1476-4598-13-214

Cited by 66 publications

(143 citation statements)

References 49 publications

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“…It was recently reported that p16 can be also regulated by Src-AKT pathway in cellular senescence in human prostate cancer cells [28]. In this study, our result indicated that the phosphorylation levels of FOXO1 and FOXO3a were also markedly increased by the co-treatment when compared to that induced by either Src or mTOR inhibitor alone (Fig 2B).…”

Section: Resultssupporting

confidence: 74%

Rapamycin Enhances the Anti-Cancer Effect of Dasatinib by Suppressing Src/PI3K/mTOR Pathway in NSCLC Cells

Chen

Luo

et al. 2015

PLoS ONE

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Src and the mammalian target of rapamycin (mTOR) signaling are commonly activated in non-small cell lung cancer (NSCLC) and hence potential targets for chemotherapy. Although the combined use of Src inhibitor Dasatinib with other chemotherapeutic agents has shown superior efficacy for cancer treatment, the mechanisms that lead to enhanced sensitivity of Dasatinib are not completely understood. In this study, we found that Rapamycin dramatically enhanced Dasatinib-induced cell growth inhibition and cell cycle G1 arrest in human lung adenocarcinoma A549 cells without affecting apoptosis. The synergistic effects were consistently correlated with the up-regulation of cyclin-dependent kinases inhibitor proteins, including p16, p19, p21, and p27, as well as the repression of Cdk4 expression and nuclear translocation. Mechanistic investigations demonstrated that FoxO1/FoxO3a and p70S6K/4E-BP1, the molecules at downstream of Src-PI3K-Akt and mTOR signaling, were significantly suppressed by the combined use of Dasatinib and Rapamycin. Restraining Src and mTOR with small interfering RNA in A549 cells further confirmed that the Src/PI3K/mTOR Pathway played a crucial role in enhancing the anticancer effect of Dasatinib. In addition, this finding was also validated by a series of assays using another two NSCLC cell lines, NCI-H1706 and NCI-H460. Conclusively, our results suggested that the combinatory application of Src and mTOR inhibitors might be a promising therapeutic strategy for NSCLC treatment.

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Section: Resultssupporting

confidence: 74%

Rapamycin Enhances the Anti-Cancer Effect of Dasatinib by Suppressing Src/PI3K/mTOR Pathway in NSCLC Cells

Chen

Luo

et al. 2015

PLoS ONE

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“…Numerous studies demonstrated the pro-senescence activity of the Akt signaling pathway [36-38]. However, the anti-senescence activity of the Akt signaling pathway has also been proposed in several types of tissues and cells, such as multipotent mesenchymal stem cells [39].…”

Section: Discussionmentioning

confidence: 99%

GLP-1 and Ghrelin Attenuate High Glucose/High Lipid-Induced Apoptosis and Senescence of Human Microvascular Endothelial Cells

Liao¹,

Yang²,

Liu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: GLP-1 and ghrelin are common appetite-regulating hormones. Both have multiple functions beyond metabolic regulation. However, the effects of GLP-1 and ghrelin on endothelial biology are not fully understood. Here, we investigate the roles of GLP-1 and ghrelin in microvascular endothelial apoptosis and senescence. Methods: Human microvascular endothelial cells (HMECs) were exposed to high glucose/high lipid (HG/HL) conditions and treated with GLP-1 or ghrelin. Cellular apoptosis, senescence, and mitochondrial function were measured. In addition, the MAPK and Akt signaling pathways were examined. Results: Both GLP-1 and ghrelin treatment decreased the number of TUNEL-positive cells and inhibited caspase-3 and PARP cleavage and mitochondrial dysfunction in HG/HL-exposed HMECs. GLP-1, but not ghrelin decreased the number of β-galactosidase (β-gal)-positive cells. Furthermore, GLP-1 and ghrelin inhibited ERK1/2, JNK1/2, and p38 signaling. GLP-1 suppressed Akt signaling, but ghrelin had no effect. Moreover, JNK1/2 and p38 inhibitors, but not ERK1/2 and Akt inhibitors, decreased the number of TUNEL-positive cells. Additionally, only the Akt inhibitor decreased the number of β-gal-positive cells. Conclusion: These results demonstrate that GLP-1 and ghrelin inhibit mitochondrial dysfunction under HG/HL conditions, and suppress endothelial apoptosis via inhibiting JNK1/2 and p38 signaling; moreover, GLP-1 alleviates endothelial senescence via inactivating Akt signaling.

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Section: Introductionmentioning

confidence: 99%

“…Depending on the concentration, androgens can promote as well as suppress cell proliferation through the regulation of the androgen receptor (AR) [4–9]. For example, cellular senescence is a natural mechanism to suppress malignant cell growth through the regulation of various tumor suppressor proteins [9–13]. In addition, exogenous and endogenous stimuli cause irreversible cell cycle arrest leading to morphological changes and altered gene expression [14, 15].…”

Section: Introductionmentioning

confidence: 99%

The activation of OR51E1 causes growth suppression of human prostate cancer cells

et al. 2016

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The development of prostate cancer (PCa) is regulated by the androgen-dependent activity of the androgen receptor (AR). Androgen-deprivation therapy (ADT) is therefore the gold standard treatment to suppress malignant progression of PCa. Nevertheless, due to the development of castration resistance, recurrence of disease after initial response to ADT is a major obstacle to successful treatment. As G-protein coupled receptors play a fundamental role in PCa physiology, they might represent promising alternative or combinatorial targets for advanced diseases. Here, we verified gene expression of the olfactory receptors (ORs) OR51E1 [prostate-specific G-protein coupled receptor 2 (PSGR2)] and OR51E2 (PSGR) in human PCa tissue by RNA-Seq analysis and RT-PCR and elucidated the subcellular localization of both receptor proteins in human prostate tissue. The OR51E1 agonist nonanoic acid (NA) leads to the phosphorylation of various protein kinases and growth suppression of the PCa cell line LNCaP. Furthermore, treatment with NA causes reduction of androgen-mediated AR target gene expression. Interestingly, NA induces cellular senescence, which coincides with reduced E2F1 mRNA levels. In contrast, treatment with the structurally related compound 1-nonanol or the OR2AG1 agonist amyl butyrate, neither of which activates OR51E1, did not lead to reduced cell growth or an induction of cellular senescence. However, decanoic acid, another OR51E1 agonist, also induces cellular senescence. Thus, our results suggest the involvement of OR51E1 in growth processes of PCa cells and its impact on AR-mediated signaling. These findings provide novel evidences to support the functional importance of ORs in PCa pathogenesis.

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Supraphysiological androgen levels induce cellular senescence in human prostate cancer cells through the Src-Akt pathway

Cited by 66 publications

References 49 publications

Rapamycin Enhances the Anti-Cancer Effect of Dasatinib by Suppressing Src/PI3K/mTOR Pathway in NSCLC Cells

Rapamycin Enhances the Anti-Cancer Effect of Dasatinib by Suppressing Src/PI3K/mTOR Pathway in NSCLC Cells

GLP-1 and Ghrelin Attenuate High Glucose/High Lipid-Induced Apoptosis and Senescence of Human Microvascular Endothelial Cells

The activation of OR51E1 causes growth suppression of human prostate cancer cells

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