Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy

Molecular Metabolism

Ángeles Juarranz¹  Salvador González¹  Mikel Portillo-Esnaola¹  María Gallego-Rentero¹  Jimena Nicolás-Morala²  Yolanda Gilaberte²  Marta Mascaraque-Checa²  José M. Cuezva² 

[1] Instituto Ramón y Cajal de Investigaciones Sanitarias, IRYCIS, Madrid, Spain;Departament of Biology, Universidad Autónoma de Madrid, Madrid, Spain;

关键词: Skin squamous cell carcinoma;    Cancer resistance;    Photodynamic therapy;    Warburg effect;    Metformin;    AKT/mTOR pathway;   

DOI  :  

来源: DOAJ

【 摘 要 】

Objective: Cancer metabolic reprogramming promotes resistance to therapies. In this study, we addressed the role of the Warburg effect in the resistance to photodynamic therapy (PDT) in skin squamous cell carcinoma (sSCC). Furthermore, we assessed the effect of metformin treatment, an antidiabetic type II drug that modulates metabolism, as adjuvant to PDT. Methods: For that, we have used two human SCC cell lines: SCC13 and A431, called parental (P) and from these cell lines we have generated the corresponding PDT resistant cells (10GT). Results: Here, we show that 10GT cells induced metabolic reprogramming to an enhanced aerobic glycolysis and reduced activity of oxidative phosphorylation, which could influence the response to PDT. This result was also confirmed in P and 10GT SCC13 tumors developed in mice. The treatment with metformin caused a reduction in aerobic glycolysis and an increase in oxidative phosphorylation in 10GT sSCC cells. Finally, the combination of metformin with PDT improved the cytotoxic effects on P and 10GT cells. The combined treatment induced an increase in the protoporphyrin IX production, in the reactive oxygen species generation and in the AMPK expression and produced the inhibition of AKT/mTOR pathway. The greater efficacy of combined treatments was also seen in vivo, in xenografts of P and 10GT SCC13 cells. Conclusions: Altogether, our results reveal that PDT resistance implies, at least partially, a metabolic reprogramming towards aerobic glycolysis that is prevented by metformin treatment. Therefore, metformin may constitute an excellent adjuvant for PDT in sSCC.

【 授权许可】

Unknown