Article Text
Abstract
Introduction Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy because of the develop of chemoresistance. Interrogation of transcriptomic data from EOC tumors revealed enrichment of lipid and cholesterol metabolism pathways in chemoresistant tumors, implicating dysregulated lipid metabolism in the development of drug resistance.
Methods To model EOC stemness, RNA sequencing was utilized to identify differentially expressed genes (DEGs) between parental and ovarian cancer sphere-forming sublines. Additionally, DEGs were delineated between cohorts of 9 chemosensitive and 10 chemoresistance patient tumors. Lipidomic analysis with LC-MS analysis in electrospray negative and positive ion mode to compare clinical specimens of chemosensitive and chemoresistant tumors was performed.
Results Between chemosensitive and chemorefractory tumors, 26 commonly upregulated pathways encompassed 8 lipid metabolism pathways. IPPA1 represented the solitary DEG at the intersection of these datasets. As IPPA1 governs a rate-limiting step in cholesterol biosynthesis, its silencing attenuated the migratory and invasive capacities of EOC cells while enhancing carboplatin sensitivity, concomitant with NDR1 repression. Reciprocally, LDL-cholesterol elicited HIF1α and downstream NDR1 induction. NDR1 overexpression promoted migratory and chemoresistant in ovarian cancer cell lines and mice model. Through lipidomic analysis, we identified distinct lipidomic patterns in chemoresistant EOC tumors compared to chemosensitive ovarian tumors.
Conclusion/Implications In summary, our data revealed aberrant lipid metabolism is a driver of chemoresistance in EOC. IPPA1/HIF1α/NDR1 signaling downstream of aberrant cholesterol metabolism is related to acquisition of chemoresistance and disease progression. Targeting the cholesterol-driven NDRG1 axis could be a viable therapeutic strategy to combat ovarian cancer.