Latent-Transforming Growth Factor β-Binding Protein 1/Transforming Growth Factor β1 Complex Drives Antitumoral Effects upon ERK5 Targeting in Melanoma

Abstract

Melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. Available treatments have improved the survival, although long-term benefits are still unsatisfactory. The mitogen-activated protein kinase ERK5 promotes melanoma growth, and ERK5 inhibition determines cellular senescence and the senescence-associated secretory phenotype. Here, latent-transforming growth factor β-binding protein 1 (LTBP1) mRNA was found to be upregulated in A375 and SK-Mel-5 BRAFV600E melanoma cells after ERK5 inhibition. In keeping with a key role of LTBP1 in regulating transforming growth factor β (TGF-β), TGF-β1 protein levels were increased in lysates and conditioned media of ERK5-knock down (KD) cells, and were reduced upon LTBP1 KD. Both LTBP1 and TGF-β1 proteins were increased in melanoma xenografts in mice treated with the ERK5 inhibitor XMD8-92. Moreover, treatment with conditioned media from ERK5-KD melanoma cells reduced cell proliferation and invasiveness, and TGF-β1-neutralizing antibodies impaired these effects. In silico datasets revealed that higher expression levels of both LTBP1 and TGFB1 mRNA are associated with better overall survival of melanoma patients, and that increased LTBP1 or TGF-β1 expression proved a beneficial role in patients treated with anti-PD1 immunotherapy, making unlikely a possible immunosuppressive role of LTBP1/TGF-β1 upon ERK5 inhibition. This study, therefore, identifies additional desirable effects of ERK5 targeting, providing evidence of an ERK5-dependent tumor suppressive role of TGF-β in melanoma.