Blockade of integrin 3 signals to reverse the stem-like phenotype and drug resistance in melanoma

PurposeCancer 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.MethodsTo identify the potential role of integrin 3 in melanoma stem cells. Flow cytometry and immunofluorescence were performed to detect the expression levels of integrin 3 and integrin 3 related signal molecules. qRT-PCR and western blotting were used to detect the signaling pathways induced by integrin 3. Colony formation analysis and melanoma-bearing mice treatment by chemotherapeutic agents and integrin 3 inhibitors were used to detect the curative effects.ResultsWe proved that integrin 3 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 3 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-B signaling pathway, leading to the stem-like phenotype and drug resistance development in melanoma. Herein, the combination of cilengitide, an integrin 3 inhibitor, and chemotherapeutic agents were capable of suppressing the tumor growth and reversing the drug resistance induced by integrin 3.ConclusionThese findings identified integrin 3 as a driver of melanoma stem-like cells with drug resistance and revealed an innovative strategy in clinic melanoma treatment.