阿托伐醌诱导的氧化应激激活卵巢癌中的磷酸戊糖途径和免疫原性细胞死亡

Atovaquone, an FDA-approved oxidative phosphorylation (OXPHOS) inhibitor, has shown promise in the treatment of epithelial ovarian cancer (EOC), the deadliest gynecologic malignancy.

However, the precise mechanisms underlying its antitumorigenic effects remain unclear.

We employed a longitudinal transcriptomic approach to characterize the molecular effects of atovaquone on EOC cells.

Our findings demonstrate that atovaquone disrupts cellular homeostasis and metabolism, activates stress responses, and primes immune recognition.

We observed temporal downregulation of genes and pathways involved in key cellular processes, such as the cell cycle and DNA replication, which correlated with reduced proliferative capacity. Atovaquone also downregulated both OXPHOS and glycolysis while upregulating the pentose phosphate pathway, suggesting a metabolic shift toward redox homeostasis restoration in response to severe oxidative stress.

Consistent with oxidative stress, we found that atovaquone activated endoplasmic reticulum (ER) stress, which is linked to immunogenic cell death. During ER stress, calreticulin, a damage-associated molecular pattern (DAMP), translocates to the plasma membrane, where it promotes immune recognition.

We observed that calreticulin was upregulated on the plasma membrane of atovaquone-treated EOC cells.

Additionally, we detected increased levels of other DAMPs, such as high mobility group box 1 (HMGB1) and mitochondrial transcription factor A (TFAM), in the supernatants of atovaquone-treated cells, indicating the release of immunogenic molecules.

Moreover, increased expression of ligands for activating receptors of NK cells was observed, and coculture experiments revealed enhanced NK cell activity toward atovaquone-treated cells. These results highlight atovaquone's potential to activate immune responses, offering a new avenue for combination therapies in EOC treatment.