CD133-Dependent Activation of Phosphoinositide 3-Kinase /AKT/Mammalian Target of Rapamycin Signaling in Melanoma Progression and Drug Resistance
Naji Kharouf,
Thomas W. Flanagan,
Abdulhadi A. Alamodi,
Youssef Al Hmada,
Sofie-Yasmin Hassan,
Hosam Shalaby,
Simeon Santourlidis,
Sarah-Lilly Hassan,
Youssef Haikel,
Mossad Megahed,
Robert T. Brodell,
Mohamed Hassan
Affiliations
Naji Kharouf
Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France
Thomas W. Flanagan
Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA 70112, USA
Abdulhadi A. Alamodi
College of Health Sciences, Jackson State University, Jackson, MS 39213, USA
Youssef Al Hmada
Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA
Sofie-Yasmin Hassan
Department of Pharmacy, Faculty of Science, Heinrich-Heine University Duesseldorf, 40225 Dusseldorf, Germany
Hosam Shalaby
Department of Urology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
Simeon Santourlidis
Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
Sarah-Lilly Hassan
Department of Chemistry, Faculty of Science, Heinrich-Heine University Duesseldorf, 40225 Dusseldorf, Germany
Youssef Haikel
Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France
Mossad Megahed
Clinic of Dermatology, University Hospital of Aachen, 52074 Aachen, Germany
Robert T. Brodell
Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA
Mohamed Hassan
Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France
Melanoma frequently harbors genetic alterations in key molecules leading to the aberrant activation of PI3K and its downstream pathways. Although the role of PI3K/AKT/mTOR in melanoma progression and drug resistance is well documented, targeting the PI3K/AKT/mTOR pathway showed less efficiency in clinical trials than might have been expected, since the suppression of the PI3K/mTOR signaling pathway-induced feedback loops is mostly associated with the activation of compensatory pathways such as MAPK/MEK/ERK. Consequently, the development of intrinsic and acquired resistance can occur. As a solid tumor, melanoma is notorious for its heterogeneity. This can be expressed in the form of genetically divergent subpopulations including a small fraction of cancer stem-like cells (CSCs) and non-cancer stem cells (non-CSCs) that make the most of the tumor mass. Like other CSCs, melanoma stem-like cells (MSCs) are characterized by their unique cell surface proteins/stemness markers and aberrant signaling pathways. In addition to its function as a robust marker for stemness properties, CD133 is crucial for the maintenance of stemness properties and drug resistance. Herein, the role of CD133-dependent activation of PI3K/mTOR in the regulation of melanoma progression, drug resistance, and recurrence is reviewed.
