Melanoma stem cell maintenance and chemo-resistance are mediated by CD133 signal to PI3K-dependent pathways

Siraj M. Jamal, Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Abdulhadi Alamodi, School of public health, Jackson State University, Jackson, MS, USA.
Renate U. Wahl, Clinic of Dermatology, University Hospital of Aachen, Aachen, Germany.
Zakaria Grada, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Mohammad Abrar Shareef, Department of Internal Medicine, Eastern Maine Medical Center, Bangor, ME, USA.
Sofie-Yasmin Hassan, Clinic of Dermatology, University Hospital of Aachen, Aachen, Germany.
Fadi Murad, Department of Epidemiology, Bloomberg School of Public Health, Baltimore, MD, USA.
Sarah-Lilly Hassan, Clinic of Dermatology, University Hospital of Aachen, Aachen, Germany.
Simeon Santourlidis, Medical Faculty, Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.
Christian R. Gomez, Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA.
Youssef Haikel, Institut National de la Santé et de la Recherche Médicale, Strasbourg, France.
Mosaad Megahed, Clinic of Dermatology, University Hospital of Aachen, Aachen, Germany.
Mohamed Hassan, Institut National de la Santé et de la Recherche Médicale, Strasbourg, France. dr.hassan@gmx.de.

Abstract

Melanoma stem cells (MSCs) are characterized by their unique cell surface proteins and aberrant signaling pathways. These stemness properties are either in a causal or consequential relationship to melanoma progression, treatment resistance and recurrence. The functional analysis of CD133 and CD133 cells in vitro and in vivo revealed that melanoma progression and treatment resistance are the consequences of CD133 signal to PI3K pathway. CD133 signal to PI3K pathway drives two downstream pathways, the PI3K/Akt/MDM2 and the PI3K/Akt/MKP-1 pathways. Activation of PI3K/Akt/MDM2 pathway results in the destabilization of p53 protein, while the activation of PI3K/Akt/MKP-1 pathway results in the inhibition of mitogen-activated protein kinases (MAPKs) JNK and p38. Activation of both pathways leads to the inhibition of fotemustine-induced apoptosis. Thus, the disruption of CD133 signal to PI3K pathway is essential to overcome Melanoma resistance to fotemustine. The pre-clinical verification of in vitro data using xenograft mouse model of MSCs confirmed the clinical relevance of CD133 signal as a therapeutic target for melanoma treatment. In conclusion, our study provides an insight into the mechanisms regulating MSCs growth and chemo-resistance and suggested a clinically relevant approach for melanoma treatment.