Regorafenib-Induced Stress Response Alters the Bioenergetic Profile of Osteosarcoma Cells and Modulates Gene Expression Associated with Metabolic regulation-a Potential Mechanism of Osteosarcoma Treatment-Related Adaptation.
骨肉瘤是儿童和青少年中最常见的原发性恶性骨肿瘤。尽管手术和多药联合化疗取得了进展，但转移性或复发性疾病患者的预后仍然较差。瑞戈非尼是一种口服多激酶抑制剂，靶向参与肿瘤增殖、血管生成和转移的信号通路，在骨肉瘤中已显示出临床前景；然而，其作用机制尚未完全阐明。我们在人骨肉瘤细胞系（MG63）和患者来源的原代细胞系（APR1）中研究了瑞戈非尼的作用。细胞分别在各自的IC浓度下处理（MG63为26 μM，APR1为42 μM）。评估了瑞戈非尼诱导的细胞活力、凋亡、迁移、侵袭和细胞周期分布的变化。使用Seahorse XF技术评估线粒体生物能量学。通过评估与癌症相关通路相关的基因和蛋白表达，以及针对关键致癌基因的RT Profiler PCR阵列，分析分子效应。瑞戈非尼在两种细胞模型中均显著降低细胞活力、迁移和侵袭，并诱导凋亡。MG63细胞表现出更高的敏感性，反映为较低的IC值。细胞周期分析显示MG63细胞发生G2/M期阻滞，而APR1细胞出现G0/G1期积聚，表明存在不同的适应性反应。在分子水平上，瑞戈非尼调节了凋亡调节因子和非编码RNA的表达。PI3K/AKT/mTOR通路的抑制主要通过抑制蛋白磷酸化而非转录下调实现。代谢分析显示，MG63细胞中通过氧化磷酸化和糖酵解产生的ATP均减少，而APR1细胞保留了糖酵解活性。转录组谱分析揭示了与肿瘤发生、缺氧、DNA损伤反应和血管生成相关基因的差异性调控。这些发现证明了瑞戈非尼在骨肉瘤中具有多方面的抗肿瘤活性，并突出了细胞背景依赖性反应。该研究为瑞戈非尼活性的分子和代谢机制提供了新见解，并支持进一步研究该药物在骨肉瘤治疗中的应用。
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Despite advances in surgery and multiagent chemotherapy, outcomes remain poor for patients with metastatic or recurrent disease. Regorafenib, an oral multikinase inhibitor targeting pathways involved in tumor proliferation, angiogenesis, and metastasis, has shown clinical promise in osteosarcoma; however, its mechanisms of action are not fully understood. We investigated the effects of regorafenib in a human osteosarcoma cell line (MG63) and a patient-derived primary cell line (APR1). Cells were treated at their respective IC concentrations (26 μM for MG63 and 42 μM for APR1). Regorafenib-induced changes in cell viability, apoptosis, migration, invasion, and cell-cycle distribution were assessed. Mitochondrial bioenergetics were evaluated using Seahorse XF technology. Molecular effects were analyzed by assessing gene and protein expression related to cancer-associated pathways and by RT Profiler PCR arrays targeting key oncogenic genes. Regorafenib significantly reduced cell viability, migration, and invasion and induced apoptosis in both cell models. MG63 cells exhibited greater sensitivity, reflected by a lower IC value. Cell-cycle analysis revealed G2/M arrest in MG63 cells and G0/G1 accumulation in APR1 cells, indicating distinct adaptive responses. At the molecular level, regorafenib modulated the expression of apoptotic regulators and noncoding RNAs. Suppression of the PI3K/AKT/mTOR pathway occurred predominantly via inhibition of protein phosphorylation rather than transcriptional downregulation. Metabolic analyses showed reduced ATP production through both oxidative phosphorylation and glycolysis in MG63 cells, while APR1 cells preserved glycolytic activity. Transcriptomic profiling revealed differential regulation of genes associated with oncogenesis, hypoxia, DNA damage response, and angiogenesis. These findings demonstrate the multifaceted antitumor activity of regorafenib in osteosarcoma and highlight cell context-dependent responses. The study provides new insights into molecular and metabolic mechanisms underlying regorafenib activity and supports further investigation of this agent in osteosarcoma therapy.
Klaudia Marcinkowska, Anna Raciborska, Bożena Obmińska-Mrukowicz, Agnieszka Śmieszek. Regorafenib-Induced Stress Response Alters the Bioenergetic Profile of Osteosarcoma Cells and Modulates Gene Expression Associated with Metabolic regulation-a Potential Mechanism of Osteosarcoma Treatment-Related Adaptation.. Cancer management and research. 2026; doi:10.2147/CMAR.S562346.
Klaudia Marcinkowska, Anna Raciborska, Bożena Obmińska-Mrukowicz, Agnieszka Śmieszek (2026). Regorafenib-Induced Stress Response Alters the Bioenergetic Profile of Osteosarcoma Cells and Modulates Gene Expression Associated with Metabolic regulation-a Potential Mechanism of Osteosarcoma Treatment-Related Adaptation.. Cancer management and research. https://doi.org/10.2147/CMAR.S562346
Klaudia Marcinkowska, Anna Raciborska, Bożena Obmińska-Mrukowicz, Agnieszka Śmieszek. Regorafenib-Induced Stress Response Alters the Bioenergetic Profile of Osteosarcoma Cells and Modulates Gene Expression Associated with Metabolic regulation-a Potential Mechanism of Osteosarcoma Treatment-Related Adaptation.[J]. Cancer management and research, 2026 doi:10.2147/CMAR.S562346.
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