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Abstract：
Platinum (Pt)-based chemotherapy is the main treatment for ovarian cancer (OC); however, most patients develop Pt resistance (Pt-R). This work shows that Pt-R OC cells increase intracellular cholesterol through uptake via the HDL receptor, scavenger receptor type B-1 (SR-B1). SR-B1 blockade using synthetic cholesterol-poor HDL-like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death and inhibition of tumor growth. Reduced cholesterol accumulation in cancer cells induces lipid oxidative stress through the reduction of glutathione peroxidase 4 (GPx4) leading to ferroptosis. In turn, GPx4 depletion induces decreased cholesterol uptake through SR-B1 and re-sensitizes OC cells to Pt. Mechanistically, GPx4 knockdown causes lower expression of the histone acetyltransferase EP300, leading to reduced deposition of histone H3 lysine 27 acetylation (H3K27Ac) on the sterol regulatory element binding transcription factor 2 (SREBF2) promoter and suppressing expression of this key transcription factor involved in the regulation of cholesterol metabolism. SREBF2 downregulation leads to decreased SR-B1 expression and diminished cholesterol uptake. Thus, chemoresistance and cancer cell survival under high ROS burden obligates high GPx4 and SR-B1 expression through SREBF2. Targeting SR-B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt-R OC.
摘要：
铂（Pt）为基础的化疗是卵巢癌（OC）的主要治疗方法；然而，大多数患者出现铂抵抗（Pt-R）。这项工作表明，Pt-ROC细胞通过HDL受体的摄取增加细胞内胆固醇，清道夫受体B型-1（SR-B1）。使用合成的胆固醇缺乏的HDL样纳米颗粒（HDLNP）的SR-B1阻断减少了胆固醇的摄取，导致细胞死亡和肿瘤生长的抑制。癌细胞中胆固醇积累的减少通过减少谷胱甘肽过氧化物酶4（GPx4）导致铁凋亡而诱导脂质氧化应激。反过来,GPx4消耗诱导通过SR-B1的胆固醇摄取减少，并使OC细胞对Pt重新敏感。机械上,GPx4敲低导致组蛋白乙酰转移酶EP300的表达降低，导致组蛋白H3赖氨酸27乙酰化（H3K27Ac）在固醇调节元件结合转录因子2（SREBF2）启动子上的沉积减少，并抑制该关键转录因子的表达参与胆固醇代谢的调节。SREBF2下调导致SR-B1表达减少和胆固醇摄取减少。因此，在高ROS负荷下的化学抗性和癌细胞存活迫使通过SREBF2的高GPx4和SR-B1表达。靶向SR-B1以调节胆固醇摄取会抑制该轴，并在Pt-ROC中在体外和体内引起铁凋亡。
