Departament of Biology, Universidad Autónoma de Madrid, Madrid, Spain; Instituto Ramón y Cajal de Investigaciones Sanitarias, IRYCIS, Madrid, Spain.
Centro de Biología Molecular-Severo Ochoa (CBMSO/CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER-ISCIII), Universidad Autónoma de Madrid, Madrid, Spain.
Mol Metab. 2022 Jun;60:101496. doi: 10.1016/j.molmet.2022.101496. Epub 2022 Apr 9.
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.
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).
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.
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.
癌症代谢重编程促进了对治疗的耐药性。在这项研究中，我们研究了瓦博格效应（Warburg effect）在皮肤鳞状细胞癌（sSCC）对光动力疗法（PDT）耐药中的作用。此外，我们评估了二甲双胍治疗的效果，二甲双胍是一种调节代谢的抗糖尿病 II 型药物，作为 PDT 的辅助治疗。
为此，我们使用了两种人 SCC 细胞系：SCC13 和 A431，称为亲本（P），并从这些细胞系中生成了相应的 PDT 耐药细胞（10GT）。
在这里，我们表明 10GT 细胞诱导代谢重编程，增强有氧糖酵解并降低氧化磷酸化活性，这可能影响对 PDT 的反应。这一结果在 P 和 10GT SCC13 肿瘤在小鼠中发展时也得到了证实。二甲双胍治疗导致 10GT sSCC 细胞中的有氧糖酵解减少和氧化磷酸化增加。最后，二甲双胍与 PDT 的联合治疗改善了对 P 和 10GT 细胞的细胞毒性作用。联合治疗诱导原卟啉 IX 产生增加、活性氧生成增加和 AMPK 表达增加，并抑制 AKT/mTOR 途径。在 P 和 10GT SCC13 细胞的异种移植中，也观察到联合治疗的疗效更高。
总之，我们的结果表明，PDT 耐药性至少部分涉及有氧糖酵解的代谢重编程，二甲双胍治疗可预防这种变化。因此，二甲双胍可能是 sSCC 中 PDT 的理想辅助治疗药物。
