Autocrine Signaling of NRP1 Ligand Galectin-1 Elicits Resistance to BRAF-Targeted Therapy in Melanoma Cells

被引:9
作者
Rizzolio, Sabrina [1 ]
Corso, Simona [1 ,2 ]
Giordano, Silvia [1 ,2 ]
Tamagnone, Luca [3 ,4 ]
机构
[1] IRCCS, Candiolo Canc Inst FPO, I-10060 Candiolo, Italy
[2] Univ Torino, Dept Oncol, Med Sch, I-10060 Candiolo, Italy
[3] Univ Cattolica Sacro Cuore, Dept Life Sci & Publ Hlth, I-00168 Rome, Italy
[4] IRCCS, Fdn Policlin Univ A Gemelli, I-00168 Rome, Italy
关键词
galectin; neuropilin; melanoma; cancer therapy; molecular biology; cell signaling; oncogenic signaling; autocrine signaling; EGFR; BRAF; NEUROPILIN-1; INHIBITOR; PROLIFERATION; ACTIVATION;
D O I
10.3390/cancers12082218
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Melanoma cells addicted to mutated BRAF oncogene activity can be targeted by specific kinase inhibitors until they develop resistance to therapy. We observed that the expression of Galectin-1 (Gal-1), a soluble ligand of Neuropilin-1 (NRP1), is upregulated in melanoma tumor samples and melanoma cells resistant to BRAF-targeted therapy. We then demonstrated that Gal-1 is a novel driver of resistance to BRAF inhibitors in melanoma and that its activity is linked to the concomitant upregulation of the NRP1 receptor observed in drug-resistant cells. Mechanistically, Gal-1 sustains increased expression of NRP1 and EGFR in drug-resistant melanoma cells. Moreover, consistent with its role as a NRP1 ligand, Gal-1 negatively controls p27 levels, a mechanism previously found to enable EGFR upregulation in cancer cells. Finally, the combined treatment with a Gal-1 inhibitor and a NRP1 blocking drug enabled resistant melanoma cell resensitization to BRAF-targeted therapy. In summary, we found that the activation of Galectin-1/NRP1 autocrine signaling is a new mechanism conferring independence from BRAF kinase activity to oncogene-addicted melanoma cells.
引用
收藏
页码:1 / 14
页数:14
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