Wu Guosheng, Ying Liang, Zhang Qian, Xiong He, Wang Jie, Chen Sitao, Yang Chen, Jin Yiyuan, Lai Zengwei, Feng Ninghan, Ge Yunjun
MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, China.
Department of Urology, Jiangnan University Medical Center, Wuxi, China.
Chin Med. 2024 Dec 26;19(1):178. doi: 10.1186/s13020-024-01050-5.
Lipid metabolism is crucial in cancer progression. Lipid droplets (LDs) generated in cancer cells can act as protective mechanisms through alleviating lipotoxicity under stress conditions. We previously developed IC2 from the Chinese medicine icaritin as an inhibitor of stearoyl-CoA desaturase 1 (SCD1). IC2 has been shown to disrupt lipid metabolism and inhibits cancer cell proliferation. However, the impact of IC2 on intracellular LDs and the potential of targeting LD formation for combination cancer therapy remain unexplored.
LD formation in cancer cells was analyzed with oil red O or BODIPY staining by microscopy. LD quantification was normalized to the cell number. IC2-induced cellular responses were revealed by transcriptional analysis, real-time PCR, and immunoblotting. Mitochondrial functions were assessed by measuring ATP production and oxygen consumption. The lipid source for LD formation was studied using lipid transporter inhibitors or lipid deprivation. The effect of inhibiting LD formation on IC2's anti-tumor effects was evaluated using MTT assays and apoptosis assays, which was subsequently validated in an in vivo xenografted tumor model.
IC2 exerted anti-tumor effects, resulting in LD formation in various cancer cells. LD formation stimulated by IC2 was independent of extracellular lipid sources and did not result from increased de novo fatty acid (FA) synthesis within the cancer cells. Transcriptional analysis indicated that IC2 disturbed mitochondrial functions, which was confirmed by impaired mitochondrial membrane potential (MMP) and reduced capacity for ATP production and oxygen consumption. Moreover, IC2 treatment led to a greater accumulation of lipids in LDs outside the mitochondria compared with the control group. IC2 inhibited the proliferation of PC3 cells and promoted the apoptosis of the cancer cells. These effects were further enhanced after inhibiting the diacylglycerol acyltransferase 1 (DGAT1), a key intracellular enzyme involved in LD formation. In PC3-xenografted mice, the DGAT1 inhibitor augmented the IC2-induced reduction in tumor growth by modulating LD formation.
LD formation is a feedback response to IC2's anti-tumor effects, which compromises the anti-tumor actions. IC2's anti-tumor efficacy can be enhanced by combining it with inhibitors targeting LD formation. This strategy may be extended to other anti-tumor agents that regulate lipid metabolism.
脂质代谢在癌症进展中至关重要。癌细胞中产生的脂滴（LDs）可通过在应激条件下减轻脂毒性而发挥保护机制。我们之前从中药淫羊藿素开发出IC2作为硬脂酰辅酶A去饱和酶1（SCD1）的抑制剂。IC2已被证明可扰乱脂质代谢并抑制癌细胞增殖。然而，IC2对细胞内脂滴的影响以及靶向脂滴形成用于联合癌症治疗的潜力仍未得到探索。
通过显微镜用油红O或BODIPY染色分析癌细胞中的脂滴形成。脂滴定量以细胞数量进行标准化。通过转录分析、实时PCR和免疫印迹揭示IC2诱导的细胞反应。通过测量ATP产生和氧气消耗评估线粒体功能。使用脂质转运抑制剂或脂质剥夺研究脂滴形成的脂质来源。使用MTT试验和凋亡试验评估抑制脂滴形成对IC2抗肿瘤作用的影响，随后在体内异种移植肿瘤模型中进行验证。
IC2发挥抗肿瘤作用，导致各种癌细胞中形成脂滴。IC2刺激的脂滴形成独立于细胞外脂质来源，并非由癌细胞内从头脂肪酸（FA）合成增加所致。转录分析表明IC2扰乱线粒体功能，这通过线粒体膜电位（MMP）受损以及ATP产生和氧气消耗能力降低得到证实。此外，与对照组相比，IC2处理导致线粒体外脂滴中脂质积累更多。IC2抑制PC3细胞增殖并促进癌细胞凋亡。在抑制二酰甘油酰基转移酶1（DGAT1）后，这些作用进一步增强，DGAT1是参与脂滴形成的关键细胞内酶。在PC3异种移植小鼠中，DGAT1抑制剂通过调节脂滴形成增强了IC2诱导的肿瘤生长抑制。
脂滴形成是对IC2抗肿瘤作用的反馈反应，这损害了抗肿瘤作用。将IC2与靶向脂滴形成的抑制剂联合使用可增强其抗肿瘤疗效。该策略可能扩展到其他调节脂质代谢的抗肿瘤药物。
