Abstract 424: FDX2-KO induces global down-regulation of iron-sulfur cluster-containing proteins and senescence-like growth arrest or death in ovarian cancer cells

Abstract Iron-Sulfur clusters (Fe-S) are synthetized in mainly mitochondria and binds to various proteins (Fe-S proteins). Fe-S proteins play important roles in various cellular functions including energy metabolism, nucleic acid synthesis or redox homeostasis. However, roles of Fe-S clusters in cancer cells are not fully understood. Here, we report that loss of Fe-S biosynthesis causes proliferation arrest with DNA-damage response or cell death depend on TP53 status in ovarian cancer (OVC) cells. CRISPR-screening of all metabolism-related genes identified that Fe-S biosynthesis is essential for OVC proliferation. We chose one of the Fe-S biosynthesis factors, FDX2, and developed a cell line that can maintain FDX2 expression doxycycline (Dox) -dependently. In these cells, FDX2-loss induced irreversible growth arrest. FDX2-KO cells also showed enlarged and flatten morphology, up-regulation of SASP factors, and DNA damage through p53/p21 pathway activation. These were all senescence like phenotypes. To know these mechanisms, we performed proteome analysis and found that FDX2-loss caused global but differential post-transcriptional down-regulation of Fe-S proteins, in turn perturbing mitochondrial respiration, iron-regulation and redox homeostasis. These results all associated with DNA damage. Furthermore, we found that FDX2-KO induced caspase dependent cell death in TP53-KO condition instead of growth arrests. These results suggest that Fe-S cluster biosynthesis is significant in OVC proliferation and fate of FDX2-KO cells depends on TP53 status (senescence or cell death). FDX2 or Fe-S biosynthesis may be a new therapeutic target of OVC. Citation Format: Shuko Miyahara, Mai Ohuchi, Miyuki Nomura, Kayoko Hayashi, Muneaki Shimada, Nobuo Yaegashi, Nobuhiro Tanuma. FDX2-KO induces global down-regulation of iron-sulfur cluster-containing proteins and senescence-like growth arrest or death in ovarian cancer cells [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 424.