Immunoregulatory protein B7-H3 promotes growth and decreases sensitivity to therapy in metastatic melanoma cells.
Karine Flem-KarlsenChristina TekleYvonne AnderssonKjersti FlatmarkØystein FodstadCaroline E Nunes-XavierPublished in: Pigment cell & melanoma research (2017)
B7-H3 (CD276) belongs to the B7 family of immunoregulatory proteins and has been implicated in cancer progression and metastasis. In this study, we found that metastatic melanoma cells with knockdown expression of B7-H3 showed modest decrease in proliferation and glycolytic capacity and were more sensitive to dacarbazine (DTIC) chemotherapy and small-molecule inhibitors targeting MAP kinase (MAPK) and AKT/mTOR pathways: vemurafenib (PLX4032; BRAF inhibitor), binimetinib (MEK-162; MEK inhibitor), everolimus (RAD001; mTOR inhibitor), and triciribidine (API-2; AKT inhibitor). Similar effects were observed in melanoma cells in the presence of an inhibitory B7-H3 monoclonal antibody, while the opposite was seen in B7-H3-overexpressing cells. Further, combining B7-H3 inhibition with small-molecule inhibitors resulted in significantly increased antiproliferative effect in melanoma cells, as well as in BRAFV600E mutated cell lines derived from patient biopsies. Our findings indicate that targeting B7-H3 may be a novel alternative to improve current therapy of metastatic melanoma.
Keyphrases
- small molecule
- signaling pathway
- cell proliferation
- monoclonal antibody
- pi k akt
- protein protein
- induced apoptosis
- squamous cell carcinoma
- small cell lung cancer
- cancer therapy
- cell cycle arrest
- papillary thyroid
- oxidative stress
- stem cells
- case report
- dna repair
- locally advanced
- radiation therapy
- long non coding rna
- cell death
- lymph node metastasis
- cell therapy
- squamous cell