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The Akt/mTOR pathway in cancer stem/progenitor cells is a potential therapeutic target for glioblastoma and neuroblastoma.

ABSTRACT: Nervous system tumors represent some of the highly aggressive cancers in both children and adults, particularly neuroblastoma and glioblastoma. Many studies focused on the pathogenic role of the Akt pathway and the mechanistic target of Rapamycin (mTOR) complex in mediating the progression of various types of cancer, which designates the Akt/mTOR signaling pathway as a master regulator for cancer. Current studies are also elucidating the mechanisms of cancer stem cells (CSCs) in replenishing tumors and explicating the strong correlation between the Akt/mTOR pathway and CSC biology. This instigates the development of novel treatments that target CSCs via inhibiting this pathway to prevent recurrence in various cancer subtypes. In accordance, neuroblastoma and glioblastoma tumors are believed to originate from stem/progenitor cells or dedifferentiated mature neural/glial cells transformed into CSCs, which warrants targeting this subpopulation of CSCs in these tumors. In our study, Triciribine and Rapamycin were used to assess the role of inhibiting two different points of the Akt/mTOR pathway in vitro on U251 (glioblastoma) and SH-SY5Y (neuroblastoma) human cell lines and their CSCs. We showed that both drugs minimally decrease the survival of U251 and SH-SY5Y cells in a 2D model, while this effect was much more pronounced in a 3D culture model. Triciribine and Rapamycin decreased migratory abilities of both cell lines and decreased their sphere-forming units (SFU) by extinguishing their CSC populations. Together, we concluded that Rapamycin and Triciribine proved to be effective in the in vitro treatment of glioblastoma and neuroblastoma, by targeting their CSC population.

SUBMITTER: Bahmad HF

PROVIDER: S-EPMC6173359 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other

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The Akt/mTOR pathway in cancer stem/progenitor cells is a potential therapeutic target for glioblastoma and neuroblastoma.

Bahmad Hisham F HF Mouhieddine Tarek H TH Chalhoub Reda M RM Assi Sahar S Araji Tarek T Chamaa Farah F Itani Muhieddine M MM Nokkari Amaly A Kobeissy Firas F Daoud Georges G Abou-Kheir Wassim W

Oncotarget 20180911 71

Nervous system tumors represent some of the highly aggressive cancers in both children and adults, particularly neuroblastoma and glioblastoma. Many studies focused on the pathogenic role of the Akt pathway and the mechanistic target of Rapamycin (mTOR) complex in mediating the progression of various types of cancer, which designates the Akt/mTOR signaling pathway as a master regulator for cancer. Current studies are also elucidating the mechanisms of cancer stem cells (CSCs) in replenishing tum ...[more]

PMID: 30323898

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Project description:Mammary adenocarcinoma, the most common cancer in female dogs, often exhibits the lymph node and lung metastases and has a higher mortality rate. However, mammary adenocarcinoma has no established treatment, except early surgical excision. Canine mammary carcinoma has many common features with human mammary carcinoma, including clinical characteristics, heterogeneity, and genetic aberrations, making it an excellent spontaneous tumor model for human breast cancer. Diverse cancers comprised heterogeneous cell populations originating from cancer stem cells (CSCs) with self-renewal ability. Therefore, in addition to conventional therapy, therapeutic strategies targeting CSCs are essential for cancer eradication. The present study aimed to extract inhibitors of canine mammary CSCs that suppress their self-renewal ability. Sphere-formation assay, which evaluates self-renewal ability, was performed for the canine mammary cancer cell lines CTBp and CNMp. The spheres formed in this assay were used in inhibitor library screening, which identified various signaling pathways such as proteosome, stress inducer, and mammalian target of rapamycin (mTOR). The present study focused on the mTOR signaling pathway. Western blotting showed higher levels of phosphorylated mTOR in sphere-forming CTBp and CNMp cells than in adherent cells. Drug sensitivity examination using the mTOR inhibitors everolimus and temsirolimus revealed dose-dependent reductions in viability among both sphere-forming cells and adherent cells. Expression of phosphorylated mTOR in adherent and sphere-forming cells decreased by everolimus and temsirolimus treatment. In mice transplanted with CTBp-derived spheres, everolimus treatment significantly decreased tumor volume compared to control. These results reveal that the mTOR signaling pathway may be a potential to be a therapeutic target in both cancer cells and CSCs. Novel therapeutic strategies for canine mammary carcinoma are expected to benefit to human breast carcinoma as well.

Project description:Breaking resistance to chemotherapy is a major goal of combination therapy in many tumors, including advanced neuroblastoma. We recently demonstrated that increased activity of the PI3K/Akt network is associated with poor prognosis, thus providing an ideal target for chemosensitization. Here we show that targeted therapy using the PI3K/mTOR inhibitor NVP-BEZ235 significantly enhances doxorubicin-induced apoptosis in neuroblastoma cells. Importantly, this increase in apoptosis was dependent on scheduling: while pretreatment with the inhibitor reduced doxorubicin-induced apoptosis, the sensitizing effect in co-treatment could further be increased by delayed addition of the inhibitor post chemotherapy. Desensitization for doxorubicin-induced apoptosis seemed to be mediated by a combination of cell cycle-arrest and autophagy induction, whereas sensitization was found to occur at the level of mitochondria within one hour of NVP-BEZ235 posttreatment, leading to a rapid loss of mitochondrial membrane potential with subsequent cytochrome c release and caspase-3 activation. Within the relevant time span we observed marked alterations in a ?30 kDa protein associated with mitochondrial proteins and identified it as VDAC1/Porin protein, an integral part of the mitochondrial permeability transition pore complex. VDAC1 is negatively regulated by the PI3K/Akt pathway via GSK3? and inhibition of GSK3?, which is activated when Akt is blocked, ablated the sensitizing effect of NVP-BEZ235 posttreatment. Our findings show that cancer cells can be sensitized for chemotherapy induced cell death - at least in part - by NVP-BEZ235-mediated modulation of VDAC1. More generally, we show data that suggest that sequential dosing, in particular when multiple inhibitors of a single pathway are used in the optimal sequence, has important implications for the general design of combination therapies involving molecular targeted approaches towards the PI3K/Akt/mTOR signaling network.

Project description:BackgroundFGFR1 regulates cell-cell adhesion and extracellular matrix architecture and acts as oncogene in several cancers. Potential cancer driver mutations of FGFR1 occur in neuroblastoma (NB), a neural crest-derived pediatric tumor arising in sympathetic nervous system, but so far they have not been studied experimentally. We investigated the driver-oncogene role of FGFR1 and the implication of N546K mutation in therapy-resistance in NB cells.MethodsPublic datasets were used to predict the correlation of FGFR1 expression with NB clinical outcomes. Whole genome sequencing data of 19 paired diagnostic and relapse NB samples were used to find somatic mutations. In NB cell lines, silencing by short hairpin RNA and transient overexpression of FGFR1 were performed to evaluate the effect of the identified mutation by cell growth, invasion and cologenicity assays. HEK293, SHSY5Y and SKNBE2 were selected to investigate subcellular wild-type and mutated protein localization. FGFR1 inhibitor (AZD4547), alone or in combination with PI3K inhibitor (GDC0941), was used to rescue malignant phenotypes induced by overexpression of FGFR1 wild-type and mutated protein.ResultsHigh FGFR1 expression correlated with low relapse-free survival in two independent NB gene expression datasets. In addition, we found the somatic mutation N546K, the most recurrent point mutation of FGFR1 in all cancers and already reported in NB, in one out of 19 matched primary and recurrent tumors. Loss of FGFR1 function attenuated invasion and cologenicity in NB cells, whereas FGFR1 overexpression enhanced oncogenicity. The overexpression of FGFR1N546K protein showed a higher nuclear localization compared to wild-type protein and increased cellular invasion and cologenicity. Moreover, N546K mutation caused the failure in response to treatment with FGFR1 inhibitor by activation of ERK, STAT3 and AKT pathways. The combination of FGFR1 and PI3K pathway inhibitors was effective in reducing the invasive and colonigenic ability of cells overexpressing FGFR1 mutated protein.ConclusionsFGFR1 is an actionable driver oncogene in NB and a promising therapy may consist in targeting FGFR1 mutations in patients with therapy-resistant NB.

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The Akt/mTOR pathway in cancer stem/progenitor cells is a potential therapeutic target for glioblastoma and neuroblastoma.

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The Akt/mTOR pathway in cancer stem/progenitor cells is a potential therapeutic target for glioblastoma and neuroblastoma.

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