Abstract
Abstract 2980: Exploiting the selenoproteome in uveal melanoma
Cancer research (Chicago, Ill.), v 84(6_Supplement), 2980
22 Mar 2024
Abstract
Abstract Uveal melanoma (UM) is a common intraocular malignancy arising from GNAQ/GNA11 mutations in uveal tract melanocytes. Although primary UM is treatable by radiation and enucleation, half of patients will develop liver metastasis. Unfortunately, patients with metastatic UM have a poor prognosis of approximately one-year - underscoring metastatic UM as one of the deadliest cancers. A strong prognostic indicator for UM liver metastases is a deletion or inactivation of the deubiquitinase BAP1, yet its specific role in disease progression is unclear. Intriguingly, upon BAP1 loss of function, the cysteine importer SLC7A11 is up regulated. Imported cysteine can be converted into glutathione serving as a cofactor for antioxidant enzymes like GPX4, a selenoprotein (SeP). SePs are a protein family characterized by having at least one selenocysteine - a selenium (Se) containing amino acid. Interestingly, the liver serves as a major hub for Se transport via Selenoprotein P (SEPP). The selenocysteine rich SEPP is secreted by hepatocytes and catabolized in recipient cells facilitating synthesis of de novo SeP. Here we hypothesize that mutant BAP1 UM utilizes the liver’s Se rich microenvironment to augment selenoproteome expression to stave off oxidative stress. Using publicly available datasets, we found patients with mutant BAP1 UM have increased expression of antioxidants proteins and genes associated with SeP expression. In a panel of BAP1 expressing and deficient UM cells, we found that BAP1 deficient cells have increased expression of SePs, suggesting a predisposition to resist oxidative stress. In the presence of exogenous Se, UM cell lines upregulate SeP expression indicating the importance of selenium availability for SeP expression. In addition, a hepatocyte cell line, and an ex vivo liver slice co-culture model was used to confirm that SEPP was produced in the liver slices and was associated with increased SeP expression in UM cells. Furthermore, we found that BAP1 null UM cells were more susceptible to GPX4 inhibition compared to wild type cells, suggesting a reliance on SeP expression. Taken together, these findings suggest that the liver associated selenoproteome expression may underpin an oxidative stress-associated therapeutic vulnerability in UM liver metastases. Citation Format: Alyssa Sanders, Camille Cunanan, Edward Hartsough. Exploiting the selenoproteome in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2980.
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Details
- Title
- Abstract 2980: Exploiting the selenoproteome in uveal melanoma
- Creators
- Alyssa Sanders - Drexel UniversityCamille Cunanan - Drexel UniversityEdward Hartsough - Drexel University
- Publication Details
- Cancer research (Chicago, Ill.), v 84(6_Supplement), 2980
- Publisher
- American Association for Cancer Research (AACR)
- Resource Type
- Abstract
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:001252656305221
- Other Identifier
- 991021889613904721
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- Web of Science research areas
- Oncology