Cited by 248Neuroblastoma Research and TreatmentsPI3K/AKT/mTOR signaling in cancerNeurofibromatosis and Schwannoma Cases

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PI3King the Lock: Targeting the PI3K/Akt/mTOR Pathway as a Novel Therapeutic Strategy in Neuroblastoma

King, David, Yeomanson, Daniel, Bryant, Helen E.·2015·Journal of Pediatric Hematology/Oncology

DOI 10.1097/mph.0000000000000329

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Abstract

Neuroblastoma is the most common extracranial cancer in childhood. High-risk neuroblastoma continues to have a poor prognosis and there is an urgent need to design biologically based therapies that specifically target the pathways responsible for malignant transformation and progression. One such pathway is the PI3K/Akt/mTOR pathway. In this article we outline the evidence for aberrant activation of the PI3K/Akt/mTOR pathway in neuroblastoma and discuss the possible mechanisms which mediate it. We also discuss the development of treatments targeting this pathway in neuroblastoma and the challenges that must be overcome before such treatments can enter routine clinical practice.

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Influential
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Nolo, R. M., Herbrich, S. M., Rao, A. U. K., Zweidler‐McKay, P. A., Kannan, S., & Gopalakrishnan, V. (2017) · Oncotarget · doi:10.18632/oncotarget.21364 · Cited by 29
“Results from Phase-1 trials of AKT inhibitor perifosine, which also inhibits ERK and JNK signaling pathways, have not yet been published [41, 45].”
Role of Regulatory Oncogenic or Tumor Suppressor miRNAs of PI3K/AKT Signaling Axis in the Pathogenesis of Colorectal Cancer
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Adenosine and Cordycepin Accelerate Tissue Remodeling Process through Adenosine Receptor Mediated Wnt/β-Catenin Pathway Stimulation by Regulating GSK3b Activity
Kim, J. J., Shin, J. Y., Choi, Y.-H., Lee, S. Y., Jin, M. H., Kim, C. D., Kang, N. G., & Lee, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115571 · Cited by 31
“The phosphorylation of Gsk3b-S9 depends on PKA and PI3K/AKT/mTOR pathways [50] and the Gsk3b-S9 phosphorylation inhibits Gsk3b activity, inhibiting the degradation of β-catenin and activating the Wnt signaling [34].”
Background
Neuronal microRNA regulation in Experimental Autoimmune Encephalomyelitis
Juźwik, C. A., Drake, S., Lécuyer, M., Johnson, R. M., Morquette, B., Zhang, Y., Charabati, M., Sagan, S. M., Bar‐Or, A., Prat, A., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-31542-y · Cited by 32
RETRACTED ARTICLE: Swainsonine represses glioma cell proliferation, migration and invasion by reduction of miR-92a expression
Sun, L., Jin, X., Xie, L., et al. (2019) · BMC Cancer · doi:10.1186/s12885-019-5425-7 · Cited by 29
Retracted
Combining thioridazine and loratadine for the treatment of gastrointestinal tumor
Chen, T., Hu, Y., Liu, B., Huang, X., Li, Q., Gao, N., Jin, Z., Jia, T., Guo, D., & Jin, G. (2017) · Oncology Letters · doi:10.3892/ol.2017.6815 · Cited by 28
Anti-tumor effect of AZD8055 against neuroblastoma cells in vitro and in vivo
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Protein tyrosine phosphatases: promising targets in pancreatic ductal adenocarcinoma
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Characterization of the in vitro cytotoxic effects of brachydins isolated from Fridericia platyphylla in a prostate cancer cell line
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“The AKT protein, which is involved in the PI3K/AKT/mTOR metabolic pathway, regulates quiescence, proliferation, and cell longevity (King, Yeomanson, and Bryant 2015) and its activity was significantly reduced in PC-3 cells after treatment with BrA and BrB.”
Background
MicroRNAs as the critical regulators of tyrosine kinase inhibitors resistance in lung tumor cells
Maharati, A., Zangouei, A. S., Khalili‐Tanha, G., & Moghbeli, M. (2022) · Cell Communication and Signaling · doi:10.1186/s12964-022-00840-4 · Cited by 28
A sketch of known and novel MYCN-associated miRNA networks in neuroblastoma
Megiorni, F., Colaiacovo, M., Cialfi, S., McDowell, H. P., Guffanti, A., Camero, S., Felsani, A., Losty, P. D., Pizer, B. L., Shukla, R., et al. (2017) · Oncology Reports · doi:10.3892/or.2017.5701 · Cited by 25
“8C, are correlated with the mTOR signalling cascade, outlining the evidence for the aberrant activation of this pathway in NB (77-79).”
Background
The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma
Lampis, S., Raieli, S., Montemurro, L., Bartolucci, D., Amadesi, C., Bortolotti, S., Angelucci, S., Scardovi, A. L., Nieddu, G., Cerisoli, L., et al. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02367-5 · Cited by 27
RETRACTED ARTICLE: Moringa isothiocyanate complexed with α-cyclodextrin: a new perspective in neuroblastoma treatment
Giacoppo, S., Iori, R., Rollin, P., et al. (2017) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-017-1876-z · Cited by 26
“B)/mammalian target of rapamycin (mTOR) pathway, one of the most potent pro-survival pathway, is involved in NBL progression and correlated also with poor prognosis [37, 38].”
Background
Retracted
TOFA induces cell cycle arrest and apoptosis in ACHN and 786-O cells through inhibiting PI3K/Akt/mTOR pathway
He, D., Sun, X., Yang, H., Li, X., & Yang, D. (2018) · Journal of Cancer · doi:10.7150/jca.26374 · Cited by 26
“PI3K activation phosphorylates Akt, which localizes in the plasma membrane [21].”
PI3K activation within ventromedial prefrontal cortex regulates the expression of drug‐seeking in two rodent species
Szumlinski, K. K., Ary, A. W., Shin, C., Wroten, M. G., Courson, J. A., Miller, B. W., Ruppert‐Majer, M. A., Hiller, J. W., Shahin, J. R., Ben‐Shahar, O., et al. (2018) · Addiction Biology · doi:10.1111/adb.12696 · Cited by 25
Response of the PI3K‐AKT signalling pathway to low salinity and the effect of its inhibition mediated by wortmannin on ion channels in turbot Scophthalmus maximus
Cui, W., Ma, A., & Wang, X. (2020) · Aquaculture Research · doi:10.1111/are.14607 · Cited by 25
Circular RNAs play an important role in late-stage gastric cancer: Circular RNA expression profiles and bioinformatics analyses
Fang, Y., Ma, M., Wang, J., Liu, X., & Wang, Y. (2017) · Tumor Biology · doi:10.1177/1010428317705850 · Cited by 25
Emerging Trends in Neuroblastoma Diagnosis, Therapeutics, and Research
Sharma, R., Yadav, J., Bhat, S. A., Musayev, A., Myrzagulova, S., Sharma, D., Padha, N., Saini, M., Tuli, H. S., & Singh, T. (2025) · Molecular Neurobiology · doi:10.1007/s12035-024-04680-w · Cited by 29
Piperine loaded zinc oxide nanocomposite inhibits the PI3K/AKT/mTOR signaling pathway via attenuating the development of gastric carcinoma: In vitroandin vivostudies
Yang, Z., Pu, M., Dong, X., Ji, F., Veeraraghavan, V. P., & Yang, H. (2020) · Arabian Journal of Chemistry · doi:10.1016/j.arabjc.2020.03.028 · Cited by 24
HnRNP-F promotes the proliferation of bladder cancer cells mediated by PI3K/AKT/FOXO1
Li, F., Xie, W., Fang, Y., Xie, K., Liu, W., Hou, L., & Tan, W. (2020) · Journal of Cancer · doi:10.7150/jca.50490 · Cited by 24
“roles in various cancers in an extensive range of cellular regulatory processes, such as cell proliferation, invasion, migration and metabolism [5, 6].”
Background
Current biomarker-associated procedures of cancer modeling-a reference in the context of IDH1 mutant glioma
Mehrjardi, N. Z., Hänggi, D., & Kahlert, U. D. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03196-0 · Cited by 23
Silencing of epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1)viasiRNA-induced cell death in glioblastoma
Serban, F., Daianu, O., Tătăranu, L. G., Artene, Ş.-A., Emami, G., Georgescu, A. M., Alexandru, O., Purcaru, Ş. O., Tache, D. E., Dănciulescu, M. M., et al. (2016) · Journal of Immunoassay and Immunochemistry · doi:10.1080/15321819.2016.1209217 · Cited by 24
“One of the most fundamental cellular signaling pathways intensely studied and explored in cancer biology is the PI3K/AKT/mTOR (phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin) pathway, considered a central regulation point in growth factor receptor signaling.([16]) In tumorigenesis, PI3K/A…”
Background
Dysbindin promotes progression of pancreatic ductal adenocarcinoma via direct activation of PI3K
Fang, C., Guo, X., Lv, X., Yin, R., Lv, X., Wang, F., Zhao, J., Bai, Q., Yao, X., & Chen, Y. (2017) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjx043 · Cited by 24
“D ow nloaded from https://academ ic.oup.com /jm cb/article-abstract/9/6/504/4356861 by guest on 15 M arch 2020 PI3K can phosphorylate and activate AKT by recruiting AKT to the plasma membrane (King et al., 2015).”
Background
Minocycline attenuates ethanol-induced cell death and microglial activation in the developing spinal cord
Ren, Z., Wang, X., Xu, M., Frank, J. A., & Luo, J. (2018) · Alcohol · doi:10.1016/j.alcohol.2018.12.002 · Cited by 25
Triptolide sensitizes cisplatin-resistant human epithelial ovarian cancer by inhibiting the phosphorylation of AKT
Huang, G., Hu, H., Zhang, Y., Zhu, Y., Liu, J., Tan, B., & Chen, T. (2019) · Journal of Cancer · doi:10.7150/jca.30669 · Cited by 23
Harnessing the role of aberrant cell signaling pathways in glioblastoma multiforme: a prospect towards the targeted therapy
Hasan, S., Mahmud, Z., Hossain, M., & Islam, S. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09996-3 · Cited by 23
“Interestingly, the activation of mTORC1 itself is influenced by Ras-related GTP binding (RAG) GTPases, which are stimulated by amino acids and recruit MAPK and mTOR activators [70].”
Neurotoxicity of local anesthetics in dentistry
Kim, E.-J., Kim, H. Y., & Ahn, J.-H. (2020) · Journal of Dental Anesthesia and Pain Medicine · doi:10.17245/jdapm.2020.20.2.55 · Cited by 23
“The activation of PI3K phosphorylates and activates serinethreonine protein kinase B (Akt), an enzyme for protection from apoptosis [41,42].”
Background
Association of a genetic variant in AKT1 gene with features of the metabolic syndrome
Eshaghi, F. S., Ghazizadeh, H., Kazami-Nooreini, S., Timar, A., Esmaeily, H., Mehramiz, M., Avan, A., & Ghayour‐Mobarhan, M. (2019) · Genes & Diseases · doi:10.1016/j.gendis.2019.03.002 · Cited by 23
“Protein kinase B (PKB, also known as AKT) is activated by phosphoinositide 3-kinase (PI3K) via phosphorylation.(10) Protein kinase B plays an important role in several cell processes, that include: regulation of metabolism, cell survival, motility, transcription and cellcycle progression.”
Background
Comparing mTOR inhibitor Rapamycin with Torin-2 within the RIST molecular-targeted regimen in neuroblastoma cells
Waetzig, R., Matthes, M., Leister, J., Penkivech, G., Heise, T., Corbacioglu, S., & Sommer, G. (2020) · International Journal of Medical Sciences · doi:10.7150/ijms.48393 · Cited by 23
“This new drug class potently inhibits both mTOR complexes and consequently may prevent AKT feedback activation [32].”
Background
Recent Trends of microRNA Significance in Pediatric Population Glioblastoma and Current Knowledge of Micro RNA Function in Glioblastoma Multiforme
Mazurek, M., Grochowski, C., Litak, J., Osuchowska, I., Maciejewski, R., & Kamieniak, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093046 · Cited by 23
Anti-Hair Loss Effect of Adenosine Is Exerted by cAMP Mediated Wnt/β-Catenin Pathway Stimulation via Modulation of Gsk3β Activity in Cultured Human Dermal Papilla Cells
Kim, J. J., Shin, J. Y., Choi, Y.-H., Kang, N. G., & Lee, S. (2022) · Molecules · doi:10.3390/molecules27072184 · Cited by 27
“Since the phosphorylation of Gsk3β-S9 was reported to depend on the PKA and PI3K/AKT/mTOR pathways [50], we examined the effects of various inhibitors for adenosine receptors (ZM241385 and PBS603), MAP kinases (KH7, H89, LY294002), and IWR-1 on Wnt reporter activities.”
Background
Thalidomide attenuates development of morphine dependence in mice by inhibiting PI3K/Akt and nitric oxide signaling pathways
Khan, M. I., Momeny, M., Ostadhadi, S., et al. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.12.002 · Cited by 22
“PI3K activate a lot of downstream effectors including plasma membrane localized protein kinase B (Akt) (King et al., 2015).”

Authors: King, D., Yeomanson, D., & Bryant, H. E.
Affiliations: Sheffield Children's Hospital (GB)
ORCID: King, David
Bryant, Helen E.
Venue: Journal of Pediatric Hematology/Oncology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2015-05
Volume: 37
Issue: 4
Pages: 245-251
ISSN: 1077-4114 (ISSN-L)
DOI: 10.1097/mph.0000000000000329
OpenAlex: W1974245465
Cited by: 248
References: 52
Citations by year: 2026: 10 · 2025: 19 · 2024: 31 · 2023: 24 · 2022: 26 · 2021: 29 · 2020: 29 · 2019: 25 · 2018: 22 · 2017: 22 · 2016: 11
FWCI: 2.46
Type: journal article
Language: en
Open access: closed
Locations: Journal of Pediatric Hematology/Oncology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Neuroblastoma Research and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Medicine › Clinical Neurology › Neurofibromatosis and Schwannoma Cases
Keywords: neuroblastoma, PI3K/AKT/mTOR pathway, high-risk neuroblastoma, PI3K inhibitors, AKT inhibitors, mTOR inhibitors, targeted therapy, childhood cancer
MeSH terms: Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Phosphoinositide-3 Kinase Inhibitors, Animals, Humans, Neuroblastoma, Signal Transduction, Phosphatidylinositol 3-Kinases, Multiprotein Complexes, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases

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PI3King the Lock: Targeting the PI3K/Akt/mTOR Pathway as a Novel Therapeutic Strategy in Neuroblastoma

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