Melanoma stem cell maintenance and chemo-resistance are mediated by CD133 signal to PI3K-dependent pathways
Authors: Sofie-Yasmin Hassan
Simeon Santourlidis
Siraj M El Jamal
Sarah-Lilly Hassan
Fadi Murad
Abdulhadi Alamodi
Christian R Gomez
Mohamed Hassan
Mohammad Abrar Shareef
Renate U Wahl
Youssef Haikel
Zakaria Grada
Mosaad Megahed
Journal: Oncogene (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Melanoma stem cells; CD133; PI3K pathway; treatment resistance; progression
Affiliations: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., School of public health, Jackson State University, Jackson, MS, USA., Clinic of Dermatology, University Hospital of Aachen, Aachen, Germany., Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Department of Internal Medicine, Eastern Maine Medical Center, Bangor, ME, USA., Department of Epidemiology, Bloomberg School of Public Health, Baltimore, MD, USA., Medical Faculty, Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany., Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA., Institut National de la Santé et de la Recherche Médicale, Strasbourg, France., Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, Strasbourg, France., Institut National de la Santé et de la Recherche Médicale, Strasbourg, France. ., Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA. .

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. 

Retracted: No

PubPeer comments:
 Figure 4. * Blue boxes: Two panels, representing cell line MV3 and primary melanoma (prMel) cells respectively, appear to look more similar than expected. Of note, the datapoints are not completely identical, and the measured percentages are different. * Red boxes: Two panels, representing metastatic melanoma specimens without or with fotemustine treatment respectively, appear to look more similar than expected. Again, the measured percentages are different. ![file] ,