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VIPAS39 confers ferroptosis resistance in ovarian cancer through exporting ACSL4

ABSTRACT: Ovarian cancer (OC), particularly its epithelial subtype (EOC), is the most lethal gynecological malignancy worldwide, with the majority of patients diagnosed at an advanced stage and a five-year survival rate below 30%. The standard treatment, primarily consisting of cytoreductive surgery and platinum-based chemotherapy, often leads to recurrence and metastasis, highlighting the urgent need for innovative therapeutic approaches. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, offers a promising avenue due to cancer cells’ heightened susceptibility compared to non-cancerous cells. This susceptibility is due to their increased iron requirements and the resultant vulnerability to peroxidation of polyunsaturated fatty acids in cell membranes. Notably, acyl-CoA synthase long-chain family member 4 (ACSL4) plays a pivotal role in this process by catalyzing the esterification of free fatty acids into membrane phospholipids, a critical step for ferroptosis induction. Our study explores the synergistic effects of interferon-gamma (IFN-γ) and arachidonic acid (AA), natural inducers of ferroptosis that increase ACSL4 expression and activity, thereby promoting cell death in EOC. We demonstrate that while some EOC cell lines are highly responsive to IFN-γ and AA, indicating effective ferroptosis induction, others show resistance, likely due to the secretion of ACSL4 via exosomes. This resistance is mediated by VIPAS39, a protein crucial for protein sorting in the endosomal pathway and exosome biogenesis. Inhibiting VIPAS39 may thus enhance the sensitivity of resistant ovarian cancer cells to ferroptosis-inducing treatments, presenting a novel therapeutic strategy to curb ovarian cancer progression. This study provides foundational insights into the heterogeneous response of EOC cells to ferroptosis and underscores the potential of targeting vesicular trafficking processes to overcome drug resistance.

ORGANISM(S): Homo Sapiens

SUBMITTER: Mo Li

PROVIDER: PXD055446 | iProX | Fri Aug 30 00:00:00 BST 2024

REPOSITORIES: iProX

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VIPAS39 confers ferroptosis resistance in epithelial ovarian cancer through exporting ACSL4.

Jiang Yuening Y Li Jie J Wang Tianzhen T Gu Xiaoyang X Li Xinyu X Liu Zhaofei Z Yue Wei W Li Mo M

EBioMedicine 20250314

<h4>Background</h4>The high mortality rate associated with epithelial ovarian cancer (EOC) is primarily due to recurrence and chemoresistance, underscoring the urgent need for innovative therapeutic approaches that leverage newly identified vulnerabilities in cancer cells. While conventional chemotherapies induce apoptosis by targeting DNA or mitotic machinery, ferroptosis represents a new distinct form of programmed cell death characterised by the accumulation of lipid peroxides.<h4>Methods</h4 ...[more]

PMID: 40088627

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Project description:Background/Objectives: Ferroptosis, an iron-dependent form of cell death, shows promise as a target for therapy-resistant cancers that exhibit increased iron metabolism. Ferroptosis is primarily characterised by lipid peroxidation within cell membranes. However, many cancers evade ferroptosis by upregulation of specialised ferroptosis defence mechanisms. This study investigates ferroptosis susceptibility in Tuberous Sclerosis Complex (TSC) cell models, and ovarian and breast cancer cell lines to identify ferroptosis resistance mechanisms and therapeutic targets. Methods: We assessed ferroptosis susceptibility using the ferroptosis inducers, RSL3 and erastin. We explored ferroptosis resistance genes using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA-sequencing was conducted to identify dysregulated ferroptosis resistance genes and to better characterise NRF2 target genes. RNA sequencing was also performed to identify gene expression after treatment with pro-ferroptotic iron-oxide nanoparticles. Results: TSC2-deficient cells exhibited resistance to RSL3 and erastin-induced ferroptosis, which correlated with increased ferroptosis defence gene expression, including NRF2 and downstream targets. NRF2 inhibition re-sensitised TSC2-deficient cells to ferroptosis, confirming its protective role. However, FSP1 inhibition did not re-sensitise TSC2-deficient angiomyolipoma kidney tumor cells to RSL3. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cell lines. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition in reversing ferroptosis resistance. Conclusions: Our findings highlight NRF2 and FSP1 as key regulators of ferroptosis resistance in TSC2-deficient and cancer cells. However, the differential efficacy of targeting these pathways suggests that patient stratification may be necessary for optimal therapeutic strategies. Targeting NRF2 and FSP1 could enhance ferroptosis susceptibility, offering a potential therapeutic approach for ferroptosis resistance cancers.

Dataset Information

VIPAS39 confers ferroptosis resistance in ovarian cancer through exporting ACSL4

Publications

VIPAS39 confers ferroptosis resistance in epithelial ovarian cancer through exporting ACSL4.

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