PI3K-AKT-mTOR-Signaling and beyond: the Complex Network in Gastroenteropancreatic Neuroendocrine Neoplasms

Briest, Franziska; Grabowski, Patricia

doi:10.7150/thno.7851

Cited by 79 publications

(79 citation statements)

References 506 publications

(296 reference statements)

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“…Therefore, miR302a may have targeted p-ERK1/2 and p-Akt through the MAPK and PI3K signaling pathways, respectively, and this may be its primary contribution to the inhibition of cell proliferation in TE-10 and ECA109 cells. Consistent with previous results, in the present study, the phosphorylation levels of Akt and ERK1/2 were significantly decreased in the miR302a mimics group (P<0.05), and increased in the miR302a inhibitor group (P<0.01) (23)(24)(25)(26). Furthermore, total Akt and ERK1/2 expression levels were also determined by western blot analysis in TE-10 and ECA109 cells, and overexpression of miR302a did not markedly differ between groups.…”

Section: Discussionsupporting

confidence: 79%

miR302a inhibits the proliferation of esophageal cancer cells through the MAPK and PI3K/Akt signaling pathways

et al. 2018

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Abstract. MicroRNAs (miRNAs/miRs) are involved in the regulation of various types of cancer, either as oncogenes or tumor suppressors. miR302a has been reported that it could suppress tumor cell proliferation by inhibiting Akt in prostate cancer. The present study examined the effect of miR302a on proliferation and invasion in esophageal cancer cell lines. The expression levels of miR302a in esophageal cancer cell lines was determined by reverse transcription-polymerase chain reaction. Subsequently, miR302a mimics were transfected into esophageal cancer cells, and cell viability and invasion were assessed by MTT and Transwell assays. In addition, the effects of miR302a on the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathways were investigated by western blot analysis. The results revealed that miR302a expression was significantly decreased in the esophageal cancer cell lines compared with a healthy esophagus epithelium cell line. Upregulation of miR302a inhibited the proliferation and invasion of esophageal cancer cells, and decreased the phosphorylation of extracellular signal-regulated kinase 1/2 and Akt. Taken together, the results of the present study indicated that miR302a overexpression inhibited the proliferation and invasion of esophageal cancer cells through suppression of the MAPK and PI3K/Akt signaling pathways, indicating the potential value of miR302a as a treatment target for human esophageal cancer.

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Section: Discussionsupporting

confidence: 79%

miR302a inhibits the proliferation of esophageal cancer cells through the MAPK and PI3K/Akt signaling pathways

et al. 2018

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“…A small, aggressive subgroup shows high proliferation rates, but most GEP-NENs demonstrate slow-growing characteristics, which makes them inaccessible to classical chemotherapies [1] . Despite their increasing incidence, GEP-NENs are counted among the rare neoplastic diseases.…”

Section: Current Therapy Options For Gastroenteropancreatic Neuroendomentioning

confidence: 99%

Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease

Freitag

Christen²,

Lewens³

et al. 2016

Neuroendocrinology

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Background: The characteristic clinical heterogeneity and mostly slow-growing behavior of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) cause problems in finding appropriate treatments. Thus, the current therapy options are not satisfactory. PKI-587 is a highly potent, novel dual inhibitor of PI3K and mTORC1/C2. Aim: We assessed the effects of PKI-587 in different GEP-NEN tumor models, including the poorly differentiated cell line LCC-18, and compared them with those of the established mTORC1 inhibitor everolimus. Methods: We treated BON, QGP-1, KRJ-I, and LCC-18 cell lines with increasing concentrations of the inhibitor PKI-587, and compared the results with those of everolimus and DMSO. We assessed the impact of the treatments on viability (WST-1 assay), on apoptotic processes (caspase 3/7 assay, JC-1), and on cell cycle regulation (flow cytometry). We determined alterations in signaling mediators by phosphor-specific Western blot analysis and conducted multiplexed gene expression analysis (nCounter® technology). Results: In all cell lines, PKI-587 dose-dependently inhibited proliferation, whereas everolimus was less effective. Treatment with PKI-587 led to cell cycle arrest and induction of apoptosis and successfully suppressed activity of the direct mTORC1 target 4E-BP1, a crucial factor for tumor genesis only partially inhibited by everolimus. Gene expression analyses revealed relevant changes of RAS, MAPK, STAT, and PI3K pathway genes after treatment. Treatment-dependent and cell line-characteristic effects on AKT/Rb/E2F signaling regarding cell cycle control and apoptosis are extensively discussed in this paper. Conclusion: PI3K/mTOR dual targeting is a promising new therapeutic approach in neuroendocrine tumor disease that should be evaluated in further clinical trials.

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“…Mutations in the PI3K pathway components were found in human cell lines that respond to rapalogs in terms of antiproliferative effects (Di Nicolantonio et al 2010). The PIK3CA gene, however, is rarely mutated in pNETs (Jiao et al 2011) and PI3K-p85a subunit mutations as well as PI3K amplifications have not been reported in NETs, so far (Briest & Grabowski 2014). Data on KRAS mutations in pNETs are also controversial: none of the 44 pNETs belonging to a Caucasian cohort was found to harbour KRAS somatic mutations (Gilbert et al 2013), which were on the contrary reported in four out of 37 consecutive Chinese pNET patients (Yuan et al 2014).…”

Section: Methodsmentioning

confidence: 99%

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

Zatelli¹,

Fanciulli²,

Malandrino³

et al. 2015

Endocrine-Related Cancer

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Medical treatment of neuroendocrine tumours (NETs) has drawn a lot of attention due to the recent demonstration of efficacy of several drugs on progression-free survival, including somatostatin analogs, small tyrosine kinase inhibitors and mTOR inhibitors (or rapalogs). The latter are approved as therapeutic agents in advanced pancreatic NETs and have been demonstrated to be effective in different types of NETs, with variable efficacy due to the development of resistance to treatment. Early detection of patients that may benefit from rapalogs treatment is of paramount importance in order to select the better treatment and avoid ineffective and expensive treatments. Predictive markers for therapeutic response are under intensive investigation, aiming at a tailored patient management and more appropriate resource utilization. This review summarizes the available data on the tissue, circulating and imaging markers that are potentially predictive of rapalog efficacy in NETs.

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PI3K-AKT-mTOR-Signaling and beyond: the Complex Network in Gastroenteropancreatic Neuroendocrine Neoplasms

Cited by 79 publications

References 506 publications

miR302a inhibits the proliferation of esophageal cancer cells through the MAPK and PI3K/Akt signaling pathways

miR302a inhibits the proliferation of esophageal cancer cells through the MAPK and PI3K/Akt signaling pathways

Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

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