Identifying the molecular mechanisms underlying radioresistance is a priority for the treatment of RMS, a myogenic tumor accounting for approximately 50% of all pediatric soft tissue sarcomas. We found that irradiation (IR) transiently increased phosphorylation of Akt1, Src, and Cav1 in human RD and RH30 lines. Synthetic inhibition of Akt1 and Src phosphorylation increased ROS levels in all RMS lines, promoting cellular radiosensitization. Accordingly, the elevated activation of the Akt1/Src/Cav1 pathway, as detected in two RD lines characterized by overexpression of a myristoylated Akt1 form (myrAkt1) or Cav1 (RDCav1), was correlated with reduced levels of ROS, higher expression of catalase, and increased radioresistance. We found that treatment with cholesterol-lowering drugs such as lovastatin and simvastatin promoted cell apoptosis in all RMS lines by reducing Akt1 and Cav1 levels and increasing intracellular ROS levels. Combining statins with IR significantly increased DNA damage and cell apoptosis as assessed by γ histone 2AX (γH2AX) staining and FACS analysis. Furthermore, in combination with the chemotherapeutic agent actinomycin D, statins were effective in reducing cell survival through increased apoptosis. Taken together, our findings suggest that the molecularly linked signature formed by Akt1, Src, Cav1, and catalase may represent a prognostic determinant for identifying subgroups of RMS patients with higher probability of recurrence after radiotherapy. Furthermore, statin-induced oxidative stress could represent a treatment option to improve the success of radiotherapy.
识别横纹肌肉瘤放射抵抗的分子机制是该疾病治疗的首要任务，横纹肌肉瘤作为一种肌源性肿瘤，约占所有儿童软组织肉瘤的50%。研究发现，在人源RD和RH30细胞系中，辐照可瞬时增加Akt1、Src和Cav1的磷酸化水平。通过合成抑制剂阻断Akt1和Src的磷酸化，可在所有横纹肌肉瘤细胞系中提高活性氧水平，从而增强细胞的放射敏感性。相应地，在两种RD细胞系（分别以过表达豆蔻酰化Akt1形式或Cav1为特征）中检测到的Akt1/Src/Cav1通路激活增强，与活性氧水平降低、过氧化氢酶表达升高以及放射抵抗性增加相关。研究发现，使用洛伐他汀和辛伐他汀等降胆固醇药物可通过降低Akt1和Cav1水平、增加细胞内活性氧水平，促进所有横纹肌肉瘤细胞系的细胞凋亡。通过γH2AX染色和流式细胞术分析评估，他汀类药物与放射治疗联合应用可显著增加DNA损伤和细胞凋亡。此外，他汀类药物与化疗药物放线菌素D联用，可通过增强细胞凋亡有效降低细胞存活率。综上所述，我们的研究结果表明，由Akt1、Src、Cav1和过氧化氢酶形成的分子关联特征，可能作为预后决定因素，用于识别放疗后复发概率较高的横纹肌肉瘤患者亚群。此外，他汀类药物诱导的氧化应激可能成为提高放疗疗效的一种治疗选择。
肿瘤(癌症)患者之家