Chronic resveratrol treatment inhibits MRC5 fibroblast SASP-related pro-tumoral effects on melanoma cells

Cellular senescence is related to organismal aging and is observed after DNA damaging cancer therapies, that induce tumor-suppressive modifications, but it is characterized by a strong increase in secreted factors, termed the “senescence-associated secretory phenotype” (SASP). Particularly, SASP from stroma senescent fibroblasts creates a cancer-favoring microenvironment, providing targets for anti-cancer interventions. In the present paper, chronic treatment (5 weeks) with 5µM resveratrol has been used to modulate senescence-related pro-tumoral features of MRC5 fibroblasts, reducing SASP-related interleukins IL1α, IL1β, IL6 and IL8; transforming-growth-factor-β (TGFβ); matrix metallo-proteinases MMP3 and MMP2; urokinase plasminogen activator (uPA); receptor proteins uPAR, IL6R, insulin growth factor receptor-1 (IGF-1R), TGFβ-R2, and CXCR4. The cellular nuclear-factor-kB (NF-kB) protein level was also reduced, confirming its role in the induction of SASP. Resveratrol pre-treated MRC5 fibroblasts were resistant to activation by TGFβ. Resveratrol treatment of senescent MRC5 induced the production of conditioned media (CM) which counteracted the pro-tumoral effect of senescent CM on A375 and A375-M6 melanoma cell proliferation and invasiveness, and reduced the expression of epithelial-to-mesenchymal transition markers related to malignant features. This experimental approach proposes a treatment that targets the senescent stromal cell phenotype to induce an anti-tumor hosting microenvironment, which is suitable for both preventive and therapeutic purposes.