mTOR pathway activation is a favorable prognostic factor in human prostate adenocarcinoma

Stelloo, Suzan; Sanders, Joyce; Nevedomskaya, Ekaterina; Jong, Jeroen de; Peters, Dennis; Leenders, Geert J.L.H. van; Jenster, Guido; Bergman, Andries M.; Zwart, Wilbert

doi:10.18632/oncotarget.8767

Cited by 18 publications

(14 citation statements)

References 28 publications

(38 reference statements)

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“…It is now appreciated that mTOR can also receive cues from other signaling pathways ( i.e ., in an Akt-independent manner) [ 20 ]. Recent data also suggest that the mTOR signaling pathway activation (evidenced by S2448 phosphorylation) is associated with a favorable prognosis in PCa [ 21 , 22 ]…”

Section: Resultsmentioning

confidence: 99%

Long non-coding RNA urothelial carcinoma associated 1 (UCA1) mediates radiation response in prostate cancer

et al. 2016

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Radioresistance remains a significant obstacle in the treatment of Prostate Cancer (PCa). To simulate the clinical scenario of irradiation resistance (IRR), we created DU145-IRR PCa cell lines by treatment with 2 Gy daily IR for 59 fractions. DU145-IRR cells acquired an aggressive phenotype as evidenced by increased clonogenic survival, tumorigenic potential and invasiveness. We performed transcriptome profiling to discover dysregulated genes in DU145-IRR cells and identified the long non-coding RNA (lncRNA), Urothelial carcinoma-associated 1 (UCA1). We first investigated the role of UCA1 in radiation response and found that UCA1 abundance was significantly higher in DU145-IRR cells compared to control cells. UCA1 siRNA-knockdown reversed the aggressive phenotype and significantly increased sensitivity to IR. UCA1 depletion inhibited growth, induced cell cycle arrest at the G2/M transition and decreased activation of the pro-survival Akt pathway. We then studied the clinical significance of UCA1 expression in two independent cohorts of PCa patients: MSKCC (130 patients) and CPC-GENE (209 patients). UCA1 over-expression was associated with decreased 5-year disease-free survival in MSKCC patients (HR = 2.9; p = 0.007) and a trend toward lower biochemical recurrence-free survival in CPC-GENE patients (HR = 2.7; p = 0.05). We showed for the first time that UCA1 depletion induces radiosensitivity, decreases proliferative capacity and disrupts cell cycle progression, which may occur through altered Akt signaling and induced cell cycle arrest at the G2/M transition. Our results indicate that UCA1 might have prognostic value in PCa and be a potential therapeutic target.

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Section: Resultsmentioning

confidence: 99%

Long non-coding RNA urothelial carcinoma associated 1 (UCA1) mediates radiation response in prostate cancer

et al. 2016

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“…PI3K/Akt and MAPK signaling pathways are important in the PCa growth and metastasis [ 31 , 32 ]. Phosphorylation of Akt and ERK is the key proteins regulating both signaling pathways, respectively.…”

Section: Discussionmentioning

confidence: 99%

Carvacrol Alleviates Prostate Cancer Cell Proliferation, Migration, and Invasion through Regulation of PI3K/Akt and MAPK Signaling Pathways

Luo

et al. 2016

Oxidative Medicine and Cellular Longevity

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TRPM7 is a potential therapeutic target for treatment of prostate cancer. In this study, we investigated the effects of nonselective TRPM7 inhibitor carvacrol on cell proliferation, migration, and invasion of prostate cancer PC-3 and DU145 cells. Our results showed that carvacrol blocked TRPM7-like currents in PC-3 and DU145 cells and reduced their proliferation, migration, and invasion. Moreover, carvacrol treatment significantly decreased MMP-2, p-Akt, and p-ERK1/2 protein expression and inhibited F-actin reorganization. Furthermore, consistently, TRPM7 knockdown reduced prostate cancer cell proliferation, migration, and invasion as well. Our study suggests that carvacrol may have therapeutic potential for the treatment of prostate cancer through its inhibition of TRPM7 channels and suppression of PI3K/Akt and MAPK signaling pathways.

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“…Stelloo et al showed that PCa patients with a high risk of relapse have low-mTOR-expressing tumors with an inactive mTOR pathway [17], and similarly, Muller et al demonstrated that the loss of p-mTOR staining was significantly linked to early biochemical recurrence across various types of cancers [26].…”

Section: Discussionmentioning

confidence: 99%

Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer

et al. 2019

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The aim of this study was to evaluate the expression of mammalian target of rapamycin (mTOR), phosphorylated-mTOR (p-mTOR), and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in prostate cancer (PCa) in order to assess intratumoral heterogeneity and correlation with clinicopathological parameters. Tissue samples from 115 patients undergoing radical prostatectomy were included in a tissue microarray comprising (A) tissue from the tumor center, (B) malignant border of the tumor, (C) tumor-adjacent benign tissue, and (D) tumor-distant benign prostatic tissue. Immune reactive scores 0-12 were correlated with clinical data in reference to localization. A meta-analysis of studies investigating the association between biochemical recurrence (BCR) and parameters of the mTOR pathway was conducted. Regardless of the location within the tumor, cancer tissue showed higher expression of mTOR, p-mTOR, and 4EB-P1 compared to benign tissue (p < 0.01). Significant differences in expression between tissue samples from groups C and D were observed for mTOR and p-mTOR. When considering expression according to the pathological stage, we observed lower p-mTOR expression in pT3 vs. pT2 (7.9 and 6.3; p = 0.01). After a median follow-up of 74.5 months (IQR 65.0-84.0), 27 patients (23.47%) developed BCR. Weak staining of mTOR was associated with shorter time to BCR (HR: 2.0; p = 0.049) after correcting for PSA and T stage. However, a significant association of mTOR expression with BCR was found for specimens from the malignant border of the tumor (B) but not the tumor center (A) (p = 0.0034 log rank). In a meta-analysis, we found that the expressions of mTOR ((RR) = 0.70; 95% CI 0.43-1.12; p = 0.13) and 4E-BP1 ((RR) = 0.86; p = 0.53) were not statistically associated with BCR, while strong staining of p-mTOR was associated with a lower risk of BCR ((RR) = 0.57; p = 0.002). All 3 markers showed stronger expression in PCa and exhibited local gradients in relation to the border of tumor and healthy tissue. Our results suggest an important role of intratumor heterogeneity for the use of mTOR parameters as biomarkers in PCa.

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mTOR pathway activation is a favorable prognostic factor in human prostate adenocarcinoma

Cited by 18 publications

References 28 publications

Long non-coding RNA urothelial carcinoma associated 1 (UCA1) mediates radiation response in prostate cancer

Long non-coding RNA urothelial carcinoma associated 1 (UCA1) mediates radiation response in prostate cancer

Carvacrol Alleviates Prostate Cancer Cell Proliferation, Migration, and Invasion through Regulation of PI3K/Akt and MAPK Signaling Pathways

Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer

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