Activation of the mammalian target of rapamycin signalling pathway in prostate cancer and its association with patient clinicopathological characteristics

Dai, Bo; Kong, Yan; Ye, Ding Wei; Guang, Chun; Zhou, Xiaoyan; Yao, Xu

doi:10.1111/j.1464-410x.2009.08538.x

Cited by 48 publications

(41 citation statements)

References 30 publications

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“…In this context, a reciprocal interplay is known to exist between mTOR and p70S6K, in the sense not only mTORC1 modulates phosphorylation of S6K at Thr 389 but is also phosphorylated by the latter at Ser 2448 in response to both mitogen-and nutrient-derived stimuli [ 31 ] . The strong positive correlation between p-AKT and p-mTOR established in the present cases lends further support to mTOR being an important effector of AKT in bladder UC, as reported in prostate cancer [ 32 ] . The interconnection between the mTOR cascade and PI3K/AKT pathway involves at least two mechanisms, i.e.…”

Section: Discussionsupporting

confidence: 87%

A comprehensive immunohistochemical and molecular approach to the PI3K/AKT/mTOR (phosphoinositide 3‐kinase/v‐akt murine thymoma viral oncogene/mammalian target of rapamycin) pathway in bladder urothelial carcinoma

Korkolopoulou¹,

Levidou²,

Trigka³

et al. 2012

BJU International

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What's known on the subject? and What does the study add?A few published studies investigating single or various PI3K/AKT/mTOR signalling components have produced inconsistent results. Moreover, PI3K regulatory subunit p85a and activated p70S6K expression levels have not been previously examined in urothelial carcinoma (UC).The present study addresses simultaneously all key members of PI3K/AKT/mTOR signalling cascade supporting a differential implication of PI3K/AKT/mTOR pathway components in urothelial tumorigenesis. Furthermore, we propose p‐4E‐BP1 as a potential prognostic marker in UC, which might assist the selection of patients more likely to benefit from chemotherapy regimens based on PI3K/AKT/mTOR pathway inhibition. Finally, the present study indicates PIK3CA/AKT1 mutational status as a potential predictive marker for time‐to‐recurrence.OBJECTIVE To perform a comprehensive simultaneous assessment of all key members of phosphoinositide 3‐kinase/v‐akt murine thymoma viral oncogene/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway along with AKT homolog 1 (AKT1) and PIK3 catalytic alpha polypeptide (PIK3CA) mutations in bladder urothelial carcinoma (UC). Published information is limited to a few studies looking into single or various combinations of members of this pathway with inconsistent results. In particular the expression status of phosphorylated (p‐)p70S6 kinase (p70S6K) and p85a subunit of PI3K has not been tested in UC. PATIENTS AND METHODS Paraffin‐embedded transurethral resection tissue from 113 patients with UC was investigated for the association of p85aPI3K, p‐AKT, p‐mTOR, p‐p70S6K and p‐4E‐BP1 (eukaryotic initiation factor 4E‐binding protein 1) expression status, as well as PIK3CA and AKT1 mutations with p‐extracellular signal‐regulated kinase 1/2 (ERK1/2), fibroblast growth factor receptor 3 (FGFR3), pathological features, recurrence and cancer‐specific survival. RESULTS With the exception of p‐p70S6K, all others components of the PI3K/AKT/mTOR pathway were upregulated in UCs as compared with normal urothelium. p‐mTOR expression strongly correlated with its upstream p‐AKT and marginally with its downstream p‐p70S6K. p85aPI3K and p‐ERK1/2 levels were also marginally correlated. PIK3CA and AKT1 mutations were distinctly uncommon and mutually exclusive, without any association with pathological features. However, the presence of AKT1 mutations was associated with increased FGFR3 levels and was restricted to p85aPI3K immunonegative cases, whereas PIK3CA mutant cases had marginally lower p85aPI3K levels. The presence of PIK3CA single or combined with AKT1 mutations was associated with shorter recurrence‐free survival in univariate survival analysis. An inverse relationship was established between p‐4E‐BP1 immunopositivity and histological grade or T category, as well as between p‐p70S6K levels and T category, the latter relationship being of marginal significance. p‐4E‐BP1 nuclear expression was marginally associated with the presence of lymphovascular invasion and adversely affected survival in multivariate, but not in univariate analysis. CONCLUSIONS PI3K/AKT/mTOR signalling components appear to be differentially implicated in urothelial tumorigenesis and, with the exception of p85aPI3K, are unrelated to the PIK3CA or AKT1 mutational status. Our findings propose p‐4E‐BP1 as a potential prognostic marker in UC independent of its association with pathological features, which might assist the selection of patients more likely to benefit from PI3K/AKT/mTOR axis inhibition. PIK3CA/AKT1 mutational status may have a place in the prediction of time‐to‐recurrence.

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Section: Discussionsupporting

confidence: 87%

A comprehensive immunohistochemical and molecular approach to the PI3K/AKT/mTOR (phosphoinositide 3‐kinase/v‐akt murine thymoma viral oncogene/mammalian target of rapamycin) pathway in bladder urothelial carcinoma

Korkolopoulou¹,

Levidou²,

Trigka³

et al. 2012

BJU International

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“…mTOR was detected mostly in the cytoplasm of epithelial cells from benign glands and cancer cells of tumor foci, with low or undetectable expression in stromal cells (Fig. 6A), which is consistent with previous studies (Dai et al 2009;Evren et al 2010;Sutherland et al 2014). No difference in mTOR cytoplasmic staining intensity between peri-tumoral and tumor samples was found (Supplemental Fig.…”

Section: Nuclear Mtor Levels Correlate With Pca Progressionsupporting

confidence: 91%

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

et al. 2017

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Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgeninduced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa.

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“…In this context, it has been hypothesised that in cancer, PTEN loss activates the Rho family proteins, leading to increased cell migration and invasion through pathways independent of AKT (43,46). In the present study, PTEN expression also failed to correlate with any other molecule of the PI3K/AKT/mTOR cascade consistent with the fact that mTOR and its downstream proteins, p-4E-BP1 and p70S6K, can also be activated by other pathways, not regulated by PTEN, such as the Raf/MAPK signaling pathway (47). However, all the PTEN mutant cases displayed cytoplasmic p-AKT immunoexpression, consistent with the abrogation of PTEN inhibitory function on PI3K ability to phosphorylate AKT (14).…”

Section: Discussionsupporting

confidence: 66%

A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

et al. 2013

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Abstract. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is upregulated in a number of human cancers, including non-small cell lung cancer (NSCLC). Its potential role in NSCLC progression provides an attractive target for anticancer therapy. The expression of phosphorylated mTOR (p-mTOR), phosphorylated AKT (p-AKT), p85α and p110γ subunits of PI3K, phosphorylated p70S6K (p-p70S6K), phosphatase and tensin homolog (PTEN) and phosphorylated 4E-BP1 (p-4E-BP1) was examined by immunohistochemistry in 102 NSCLC specimens. The results were correlated with clinicopathological features. We also examined 61 of our cases for the presence of PIK3CA, AKT1, PTEN and K-RAS mutations. A common PIK3CA mutation was detected at exon 9 in 2 samples (p.E545K), whereas another sample displayed a rare mutation (p.D1018N). Furthermore, 10 out of 54 cases (18.5%) had a K-RAS mutation at codon 12, 5 had a PTEN mutation (exons 7 and 8) and 1 case had an AKT1 mutation (p.E17K). PTEN mutations were associated with nodal metastases.

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Activation of the mammalian target of rapamycin signalling pathway in prostate cancer and its association with patient clinicopathological characteristics

Cited by 48 publications

References 30 publications

A comprehensive immunohistochemical and molecular approach to the PI3K/AKT/mTOR (phosphoinositide 3‐kinase/v‐akt murine thymoma viral oncogene/mammalian target of rapamycin) pathway in bladder urothelial carcinoma

A comprehensive immunohistochemical and molecular approach to the PI3K/AKT/mTOR (phosphoinositide 3‐kinase/v‐akt murine thymoma viral oncogene/mammalian target of rapamycin) pathway in bladder urothelial carcinoma

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

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