Ji Zhiwei, Moore Jade, Devarie-Baez Nelmi O, Lewis Joshua, Wu Hanzhi, Shukla Kirtikar, Lopez Elsa I Silva, Vitvitsky Victor, Key Chia-Chi Chuang, Porosnicu Mercedes, Kemp Melissa L, Banerjee Ruma, Parks John S, Tsang Allen W, Zhou Xiaobo, Furdui Cristina M
Division of Radiologic Sciences - Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Winston-Salem, NC, United States.
Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.
Front Oncol. 2023 Jan 4;12:946320. doi: 10.3389/fonc.2022.946320. eCollection 2022.
Redox metabolism is increasingly investigated in cancer as driving regulator of tumor progression, response to therapies and long-term patients' quality of life. Well-established cancer therapies, such as radiotherapy, either directly impact redox metabolism or have redox-dependent mechanisms of action defining their clinical efficacy. However, the ability to integrate redox information across signaling and metabolic networks to facilitate discovery and broader investigation of redox-regulated pathways in cancer remains a key unmet need limiting the advancement of new cancer therapies. To overcome this challenge, we developed a new constraint-based computational method (COSM) and applied it to a Head and Neck Squamous Cell Cancer (HNSCC) model of radiation resistance. This novel integrative approach identified enhanced capacity for HS production in radiation resistant cells and extracted a key relationship between intracellular redox state and cholesterol metabolism; experimental validation of this relationship highlights the importance of redox state in cellular metabolism and response to radiation.
氧化还原代谢在癌症研究中越来越受到关注，它是肿瘤进展、对治疗的反应以及患者长期生活质量的驱动调节因子。成熟的癌症治疗方法，如放射疗法，要么直接影响氧化还原代谢，要么具有依赖氧化还原的作用机制来决定其临床疗效。然而，整合信号传导和代谢网络中的氧化还原信息，以促进对癌症中氧化还原调节途径的发现和更广泛研究的能力，仍然是一个关键的未满足需求，限制了新癌症治疗方法的进展。为了克服这一挑战，我们开发了一种新的基于约束的计算方法（COSM），并将其应用于头颈部鳞状细胞癌（HNSCC）的辐射抗性模型。这种新颖的综合方法确定了辐射抗性细胞中HS产生能力的增强，并提取了细胞内氧化还原状态与胆固醇代谢之间的关键关系；对这种关系的实验验证突出了氧化还原状态在细胞代谢和对辐射反应中的重要性。
