Osnat Ashur‐Fabian

The selenoenzyme type I iodothyronine deiodinase: a new tumor suppressor in ovarian cancer

The selenoenzyme type I iodothyronine deiodinase (DIO1) catalyzes removal of iodine atoms from thyroid hormones. Although DIO1 action is reported to be disturbed in several malignancies, no work has been conducted in high‐grade serous ovarian carcinoma (HGSOC), the most lethal gynecologic cancer. We studied DIO1 expression in HGSOC patients [The Cancer Genome Atlas (TCGA) data and tumor tissues], human cell lines (ES‐2 and Kuramochi), normal Chinese hamster ovarian cells (CHO‐K1), and normal human fallopian tube cells (FT282 and FT109). To study its functional role, DIO1 was overexpressed, inhibited [by propylthiouracil (PTU)], or knocked down (KD), and cell count, proliferation, apoptosis, cell viability, and proteomics analysis were performed. Lower DIO1 levels were observed in HGSOC compared to normal cells and tissues. TCGA analyses confirmed that low DIO1 mRNA expression correlated with worse survival and therapy resistance in patients. Silencing or inhibiting the enzyme led to enhanced ovarian cancer proliferation, while an opposite effect was shown following DIO1 ectopic expression. Proteomics analysis in DIO1‐KD cells revealed global changes in proteins that facilitate tumor metabolism and progression. In conclusion, DIO1 expression and ovarian cancer progression are inversely correlated, highlighting a tumor suppressive role for this enzyme and its potential use as a biomarker in this disease.

DIO3 depletion attenuates ovarian cancer growth via reduced glycolysis and alterations in glutamine metabolism

Metabolic reprogramming emerges as a central driver of therapy resistance and survival disadvantage in ovarian cancer. We recently demonstrated that inhibiting the enzyme Deiodinase type 3 (DIO3) reduces ovarian cancer growth, although the underlying mechanism remains unclear. We studied DIO3 role in metabolism in genetically manipulated ovarian cancer cells using protein expression analysis, integrative proteomics, endogenous and extracellular metabolomics, metabolic assays including lactate and glutamate secretion, reactive oxygen species (ROS) production and the Seahorse Cell Mito Stress test. We reveled that inhibiting DIO3 suppresses glycolysis while enhancing ATP production through oxidative phosphorylation (OXPHOS). We corroborated these findings using two models of ovarian cancer xenografts, demonstrating a marked reduction in glycolytic proteins upon silencing or inhibiting DIO3 using our first in class small molecule. Moreover, altered glutamine metabolism was also documented, favoring urea cycle and TCA cycle engagement over antioxidant production, accompanied by elevated ROS. Intriguingly, DIO3 depletion in fallopian tube cells, the precursor of HGSOC, displayed distinct metabolic adaptations, including enhanced glycolysis and lipid metabolism, suggesting tissue-specific roles for DIO3. These collective findings position DIO3 as a potential regulator of ovarian cancer metabolism, with implications for targeting this enzyme to disrupt tumor energetics as a novel therapeutic approach.