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

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.

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Fig. 1: MSCs is characterized by their self-renewal potency and chemo-resistance.
Fig. 2: MSCs confirring resistance to fotemustine-induced apoptosis.
Fig. 3: Fotemustine-induced apoptosis is associated with the los of mitocondrial membrane potential.
Fig. 4: Fotemustine-induced apoptosis is associated with the accumulation of ROS.
Fig. 5: Proposed model for fotemustine (Fot.) induced effects in cells.

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Acknowledgements

This work was supported by grants from German Research Foundation (HA 5081/3-1), from L’ Alsace contre le cancer, France, German cancer research foundation (10-2202-Ha 1) to MH.

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Jamal, S.M.E., Alamodi, A., Wahl, R.U. et al. Melanoma stem cell maintenance and chemo-resistance are mediated by CD133 signal to PI3K-dependent pathways. Oncogene 39, 5468–5478 (2020). https://doi.org/10.1038/s41388-020-1373-6

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