Targeting Squalene Epoxidase Interrupts Homologous Recombination via the ER Stress Response and Promotes Radiotherapy Efficacy

Authors

• Zhipeng Hong, The Ohio State University
• Tao Liu, The Ohio State University
• Lingfeng Wan, The Ohio State University
• Pengyan Fa, The Ohio State University
• Pankaj Kumar, The Ohio State University
• Yanan Cao, University of Kentucky
• Chandra Bhushan Prasad, The Ohio State University
• Zhaojun Qiu, The Ohio State University
• Joseph Liu, The Ohio State University
• Hongbing Wang, University of Maryland
• Zaibo Li, The Ohio State University
• Qi-En Wang, The Ohio State University
• Peixuan Guo, The Ohio State University
• Deliang Guo, The Ohio State University
• Ayse S. Yilmaz, The Ohio State University
• Lanchun Lu, The Ohio State University
• Ioanna Papandreou, The Ohio State University
• Naduparambil K. Jacob, The Ohio State University
• Chunhong Yan, Augusta University Medical
• Qing-Bai She, University of Kentucky

Abstract

Over 50% of all patients with cancer are treated with radiotherapy. However, radiotherapy is often insufficient as a monotherapy and requires a nontoxic radiosensitizer. Squalene epoxidase (SQLE) controls cholesterol biosynthesis by converting squalene to 2,3-oxidosqualene. Given that SQLE is frequently overexpressed in human cancer, this study investigated the importance of SQLE in breast cancer and non–small cell lung cancer (NSCLC), two cancers often treated with radiotherapy. SQLE-positive IHC staining was observed in 68% of breast cancer and 56% of NSCLC specimens versus 15% and 25% in normal breast and lung tissue, respectively. Importantly, SQLE expression was an independent predictor of poor prognosis, and pharmacologic inhibition of SQLE enhanced breast and lung cancer cell radiosensitivity. In addition, SQLE inhibition enhanced sensitivity to PARP inhibition. Inhibition of SQLE interrupted homologous recombination by suppressing ataxia-telangiectasia mutated (ATM) activity via the translational upregulation of wild-type p53-induced phosphatase (WIP1), regardless of the p53 status. SQLE inhibition and subsequent squalene accumulation promoted this upregulation by triggering the endoplasmic reticulum (ER) stress response. Collectively, these results identify a novel tumor-specific radiosensitizer by revealing unrecognized cross-talk between squalene metabolites, ER stress, and the DNA damage response. Although SQLE inhibitors have been used as antifungal agents in the clinic, they have not yet been used as antitumor agents. Repurposing existing SQLE-inhibiting drugs may provide new cancer treatments.

Document Type

Article

Publication Date

4-1-2022

Notes/Citation Information

Only the first 20 authors and the author(s) affiliated with the University of Kentucky are listed in the author section above. For the complete list of authors, please download this article.

Digital Object Identifier (DOI)

https://doi.org/10.1158/0008-5472.CAN-21-2229

Repository Citation

Hong, Zhipeng; Liu, Tao; Wan, Lingfeng; Fa, Pengyan; Kumar, Pankaj; Cao, Yanan; Prasad, Chandra Bhushan; Qiu, Zhaojun; Liu, Joseph; Wang, Hongbing; Li, Zaibo; Wang, Qi-En; Guo, Peixuan; Guo, Deliang; Yilmaz, Ayse S.; Lu, Lanchun; Papandreou, Ioanna; Jacob, Naduparambil K.; Yan, Chunhong; and She, Qing-Bai, "Targeting Squalene Epoxidase Interrupts Homologous Recombination via the ER Stress Response and Promotes Radiotherapy Efficacy" (2022). Pharmacology and Nutritional Sciences Faculty Publications. 140.
https://uknowledge.uky.edu/pharmacol_facpub/140