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. Significance: Squalene epoxidase inhibitors are novel tumor-specific radiosensitizers that promote ER stress and suppress homologous recombination, providing a new potential therapeutic approach to enhance radiotherapy efficacy.
| Original language | English |
|---|---|
| Pages (from-to) | 1298-1312 |
| Number of pages | 15 |
| Journal | Cancer Research |
| Volume | 82 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 1 2022 |
Bibliographical note
Funding Information:The authors thank Dr. Feng Geng from D. Guo’s lab for assisting with cholesterol detection assay and lipid droplet staining and quantification. They thank Dr. Linlin Yang from Dr. Terence M. Williams’ lab for assisting with the mouse radiation. The authors thank pathologist Dr. Yu Wang from Dr. Allan Tsung’s lab for providing pathologic assessment of mouse stomach tissues and taking representative images. This work was partially funded by the NIH/NCI (grant nos. R21CA226317, R21 CA241242, R01CA240374, and R01CA249198), the America Lung Cancer Association, and the Breast Cancer Alliance and the Ohio State University James Comprehensive Cancer Intramural Research Program (Pelotonia; to J. Zhang). Pathology services were provided by the Comparative Pathology and Digital Imaging Shared Resource, Department of Veterinary Biosciences and the Comprehensive Cancer Center, The Ohio State University and supported in part by grant P30 CA16058 (NCI). The project was also supported by the National Center for Advancing Translational Sciences (grant no. UL1TR002733). The content is solely the authors’ responsibility and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the NIH. A startup fund from The First Affiliated Hospital of Sun Yat-sen University was provided to Z. Ma.
Funding Information:
Y. Cao reports grants from NIH during the conduct of the study. P. Guo reports grants from NIH during the conduct of the study and nonfinancial support from ExonanoRNA, LLC, outside the submitted work; in addition, P. Guo has a patent for RNA Nanotechnology for cancer therapy pending; and P. Guo is the cofounder of ExonanoRNA, LLC, and its subsidiary Weina Biomedical Inc.; the consultant and licensor of Oxford Nanopore Technology; and the cofounder of P&Z. N.K. Jacob reports other support from Capture Collective Inc. outside the submitted work. C. Yan reports grants from NIH/NCI and grants from the U.S. Department of Defense during the conduct of the study. Q.-B. She reports grants from NIH during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
The authors thank Dr. Feng Geng from D. Guo's lab for assisting with cholesterol detection assay and lipid droplet staining and quantification. They thank Dr. Linlin Yang from Dr. Terence M. Williams' lab for assisting with the mouse radiation. The authors thank pathologist Dr. Yu Wang from Dr. Allan Tsung's lab for providing pathologic assessment of mouse stomach tissues and taking representative images. This work was partially funded by the NIH/NCI (grant nos. R21CA226317, R21 CA241242, R01CA240374, and R01CA249198), the America Lung Cancer Association, and the Breast Cancer Alliance and the Ohio State University James Comprehensive Cancer Intramural Research Program (Pelotonia; to J. Zhang). Pathology services were provided by the Comparative Pathology and Digital Imaging Shared Resource, Department of Veterinary Biosciences and the Comprehensive Cancer Center, The Ohio State University and supported in part by grant P30 CA16058 (NCI). The project was also supported by the National Center for Advancing Translational Sciences (grant no. UL1TR002733). The content is solely the authors' responsibility and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the NIH. A startup fund from The First Affiliated Hospital of Sun Yat-sen University was provided to Z. Ma.
Publisher Copyright:
© 2022 American Association for Cancer Research
ASJC Scopus subject areas
- Oncology
- Cancer Research
