Redox integration of signaling and metabolism in a head and neck cancer model of radiation resistance using COSMRO

Zhiwei Ji; Jade Moore; Nelmi O Devarie-Baez; Joshua Lewis; Hanzhi Wu; Kirtikar Shukla; Elsa I Silva Lopez; Victor Vitvitsky; Chia-Chi Chuang Key; Mercedes Porosnicu; Melissa L Kemp; Ruma Banerjee; John S Parks; Allen W Tsang; Xiaobo Zhou; Cristina M Furdui

doi:10.3389/fonc.2022.946320

Redox integration of signaling and metabolism in a head and neck cancer model of radiation resistance using COSM^RO

Front Oncol. 2023 Jan 4:12:946320. doi: 10.3389/fonc.2022.946320. eCollection 2022.

Authors

Zhiwei Ji¹, Jade Moore², Nelmi O Devarie-Baez², Joshua Lewis^{3

4}, Hanzhi Wu², Kirtikar Shukla², Elsa I Silva Lopez², Victor Vitvitsky⁵, Chia-Chi Chuang Key², Mercedes Porosnicu⁶, Melissa L Kemp^{3

4}, Ruma Banerjee⁵, John S Parks², Allen W Tsang², Xiaobo Zhou¹, Cristina M Furdui²

Affiliations

¹ Division of Radiologic Sciences - Center for Bioinformatics and Systems Biology, Wake Forest School of Medicine, Winston-Salem, NC, United States.
² Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States.
³ The Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States.
⁴ Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, United States.
⁵ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory School of Medicine, Atlanta, GA, United States.
⁶ Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, United States.

Abstract

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^ro) and applied it to a Head and Neck Squamous Cell Cancer (HNSCC) model of radiation resistance. This novel integrative approach identified enhanced capacity for H₂S 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.

Keywords: cholesterol metabolism; flux balance analysis; head and neck cancer; mixed integer programming; redox metabolism; steroidogenesis, radiation response.

Abstract

Grants and funding