Oncotarget

Research Papers:

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

Hisham F. Bahmad, Tarek H. Mouhieddine, Reda M. Chalhoub, Sahar Assi, Tarek Araji, Farah Chamaa, Muhieddine M. Itani, Amaly Nokkari, Firas Kobeissy, Georges Daoud and Wassim Abou-Kheir _

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Oncotarget. 2018; 9:33549-33561. https://doi.org/10.18632/oncotarget.26088

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Abstract

Hisham F. Bahmad1,*, Tarek H. Mouhieddine1,3,*, Reda M. Chalhoub1,4,*, Sahar Assi1, Tarek Araji1, Farah Chamaa1, Muhieddine M. Itani1, Amaly Nokkari2, Firas Kobeissy2, Georges Daoud1 and Wassim Abou-Kheir1

1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon

2Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon

3Current Address: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

4Current Address: Medical Scientist Training Program, College of Medicine, Medical University of South Carolina, Charleston, SC, USA

*These authors contributed equally to this work

Correspondence to:

Wassim Abou-Kheir, email: [email protected]

Georges Daoud, email: [email protected]

Keywords: glioblastoma; neuroblastoma; rapamycin; triciribine; cancer stem cell

Received: April 07, 2018     Accepted: August 23, 2018     Published: September 11, 2018

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.


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