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Erschienen in:
09.01.2019 | Original Article
Blockade of integrin β3 signals to reverse the stem-like phenotype and drug resistance in melanoma
Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2019
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Purpose
Cancer cells with stem-like phenotype are frequently proliferative and show high resistance to chemotherapeutic agents. Specific cell markers to identify the cancer stem cells and reverse the drugs resistance are urgent needs in clinic cancer treatment.
Methods
To identify the potential role of integrin β3 in melanoma stem cells. Flow cytometry and immunofluorescence were performed to detect the expression levels of integrin β3 and integrin β3 related signal molecules. qRT-PCR and western blotting were used to detect the signaling pathways induced by integrin β3. Colony formation analysis and melanoma-bearing mice treatment by chemotherapeutic agents and integrin β3 inhibitors were used to detect the curative effects.
Results
We proved that integrin β3 could serve as a marker of stem-like cancer cells in melanoma, along with the acquired chemotherapeutic drugs resistance. Furthermore, we observed that the membrane–proximal complex of integrin β3 with KRAS and Galectin-3 on the surface of melanoma cancer cells could recruit the RalB, resulting in the activation of TBK1. The phosphorylated TBK1 facilitates the activation of NF-κB signaling pathway, leading to the stem-like phenotype and drug resistance development in melanoma. Herein, the combination of cilengitide, an integrin β3 inhibitor, and chemotherapeutic agents were capable of suppressing the tumor growth and reversing the drug resistance induced by integrin β3.
Conclusion
These findings identified integrin β3 as a driver of melanoma stem-like cells with drug resistance and revealed an innovative strategy in clinic melanoma treatment.