Abstract：
Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that displays highly aggressive with poor prognosis. Owing to the limited targets and drugs for TNBC clinical therapy, it is necessary to investigate the factors regulating cancer progression and develop novel therapies for cancer treatment. Ferroptosis, a nonapoptotic form of programmed cell death characterized by accumulation of iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various cancer-related signaling pathways. Recently, considerable progress has been made in demonstrating the critical role of lipid metabolism in regulating ferroptosis, indicating potential combinational therapeutic strategies for cancer treatment. In this study, by drug combination screen of lipid metabolism compounds with ferroptosis inducers in decreasing TNBC cell viability, we found potent synergy of the CB1 antagonist rimonabant with erastin/(1 S, 3 R)-RSL3 (RSL3) in inhibiting TNBC cell growth both in vitro and in vivo via promoting the levels of lipid peroxides, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) and cytosolic reactive oxygen species (ROS) production, enhancing intracellular glutathione (GSH) depletion and inducing G1 cell cycle arrest. We identified that inhibition of CB1 promoted the effect of erastin/RSL3 on inducing ferroptosis and enhanced their inhibitory effect on tumor growth. Using RNA-Seq, fatty acid analyses and functional assays, we found that CB1 regulated stearoyl-CoA desaturase 1 (SCD1)- and fatty acyl desaturase 2 (FADS2)-dependent fatty acid metabolism via phosphatidylinositol 3 kinase (PI3K)-AKT and mitogen-activated protein kinase (MAPK) signaling pathways to modulate ferroptosis sensitivity in TNBC cells. These data demonstrate that dual targeting of CB1 and ferroptosis could be a promising therapeutic strategy for TNBC.
摘要：
三阴性乳腺癌（TNBC）是一种异质性的乳腺癌亚型，表现出高度侵袭性，预后不良。由于TNBC临床治疗的靶点和药物有限,有必要研究调节癌症进展的因素，并开发癌症治疗的新疗法。Ferroptosis,程序性细胞死亡的非凋亡形式，其特征在于磷脂的铁依赖性过氧化的积累，受细胞代谢调节，氧化还原稳态，和各种癌症相关的信号通路。最近,在证明脂质代谢在调节铁凋亡中的关键作用方面已经取得了相当大的进展，表明癌症治疗的潜在组合治疗策略。在这项研究中,通过药物联合筛选脂质代谢化合物与铁凋亡诱导剂，降低TNBC细胞活力，我们发现CB1拮抗剂利莫那班与erastin/（1S，3R）-RSL3（RSL3）通过促进脂质过氧化物水平在体外和体内抑制TNBC细胞生长，丙二醛（MDA），4-羟基壬烯醛（4-HNE）和胞质活性氧（ROS）的产生，增强细胞内谷胱甘肽（GSH）消耗并诱导G1细胞周期停滞。我们确定，CB1的抑制促进了erastin/RSL3诱导铁凋亡的作用，并增强了它们对肿瘤生长的抑制作用。使用RNA-Seq，脂肪酸分析和功能分析，我们发现CB1通过磷脂酰肌醇3激酶(PI3K)-AKT和丝裂原活化蛋白激酶(MAPK)信号通路调节硬脂酰辅酶A去饱和酶1(SCD1)和脂肪酰去饱和酶2(FADS2)依赖性脂肪酸代谢,从而调节TNBC细胞的铁凋亡敏感性.这些数据表明CB1和铁凋亡的双重靶向可能是TNBC的有希望的治疗策略。
