AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy.
AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy.
复制标题
AKR1C3 依赖性脂滴形成赋予肝细胞癌细胞对靶向治疗的适应性。
作者：
Wu C;Dai C;Li X;Sun M;Chu H;Xuan Q;Yin Y;Fang C;Yang F;Jiang Z;Lv Q;He K;Qu Y;Zhao B;Cai K;Zhang S;Sun R;Xu G;Zhang L;Sun S;Liu Y
原理：脂滴（LD）形成增加与各种类型癌症的肿瘤转移、干性和化疗耐药性有关。在这里，我们发现LD的形成是肝细胞癌（HCC）细胞适应索拉非尼的关键。我们的目的是研究肝细胞癌中LD的功能及其调控机制。研究方法：通过代谢组学和蛋白质组学在索拉非尼耐药的HCC细胞中筛选负责LD形成的关键蛋白，并通过免疫印迹和免疫荧光染色进一步验证。通过基于CRISPR/Cas9的基因编辑评估AKR 1C 3的生物学功能。用氘标记棕榈酸酯或碳标记葡萄糖进行同位素示踪分析，以研究脂肪酸（FA）和葡萄糖碳通量。进行海马分析以评估糖酵解通量和线粒体功能。选择性AKR 1C 3抑制剂用于评估AKR 1C 3抑制对HCC肿瘤生长和自噬诱导的影响。结果：我们发现，长期索拉非尼治疗损害脂肪酸氧化（FAO），导致肝细胞癌细胞中的LD积累。在培养的HCC细胞中使用多组学分析，我们确定醛酮还原酶AKR 1C 3负责HCC中LD的积累。AKR 1C 3的遗传丢失完全耗尽LD含量，将FA通量引导至磷脂、鞘脂和线粒体。此外，我们发现AKR 1C 3依赖性LD积累是减轻索拉非尼诱导的线粒体脂毒性和功能障碍所必需的。药理学抑制AKR 1C 3活性可立即诱导自噬依赖性LD催化剂，导致索拉非尼耐药HCC克隆中线粒体分裂和凋亡。值得注意的是，AKR 1C 3表达的操纵足以驱动FAO和糖酵解之间的代谢转换。结论：我们的研究结果表明，AKR 1C 3依赖性LD的形成是通过调节脂质和能量稳态来适应索拉非尼的关键。AKR 1C 3依赖性LD积累通过调节脂肪吞噬作用保护HCC细胞免受索拉非尼诱导的线粒体脂毒性以AKR 1C 3为靶点可能是一种有前途的肝癌治疗策略。
Rationale: Increased lipid droplet (LD) formation has been linked to tumor metastasis, stemness, and chemoresistance in various types of cancer. Here, we revealed that LD formation is critical for the adaptation to sorafenib in hepatocellular carcinoma (HCC) cells. We aim to investigate the LD function and its regulatory mechanisms in HCC. Methods: The key proteins responsible for LD formation were screened by both metabolomics and proteomics in sorafenib-resistant HCC cells and further validated by immunoblotting and immunofluorescence staining. Biological function of AKR1C3 was evaluated by CRISPR/Cas9-based gene editing. Isotopic tracing analysis with deuterium3-labeled palmitate or carbon13-labeled glucose was conducted to investigate fatty acid (FA) and glucose carbon flux. Seahorse analysis was performed to assess the glycolytic flux and mitochondrial function. Selective AKR1C3 inhibitors were used to evaluate the effect of AKR1C3 inhibition on HCC tumor growth and induction of autophagy. Results: We found that long-term sorafenib treatment impairs fatty acid oxidation (FAO), leading to LD accumulation in HCC cells. Using multi-omics analysis in cultured HCC cells, we identified that aldo-keto reductase AKR1C3 is responsible for LD accumulation in HCC. Genetic loss of AKR1C3 fully depletes LD contents, navigating FA flux to phospholipids, sphingolipids, and mitochondria. Furthermore, we found that AKR1C3-dependent LD accumulation is required for mitigating sorafenib-induced mitochondrial lipotoxicity and dysfunction. Pharmacologic inhibition of AKR1C3 activity instantly induces autophagy-dependent LD catabolism, resulting in mitochondrial fission and apoptosis in sorafenib-resistant HCC clones. Notably, manipulation of AKR1C3 expression is sufficient to drive the metabolic switch between FAO and glycolysis. Conclusions: Our findings revealed that AKR1C3-dependent LD formation is critical for the adaptation to sorafenib in HCC through regulating lipid and energy homeostasis. AKR1C3-dependent LD accumulation protects HCC cells from sorafenib-induced mitochondrial lipotoxicity by regulating lipophagy. Targeting AKR1C3 might be a promising therapeutic strategy for HCC tumors.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
4.6
作者：
Lettiero B;Inasu M;Kimbung S;Borgquist S
通讯作者：
Borgquist S
DOI：
10.1016/0006-291x(91)90967-c
发表时间：
1991-08-15
影响因子：
3.1
作者：
JAKOBS, BS;WANDERS, RJA
通讯作者：
WANDERS, RJA
影响因子：
5.1
作者：
Matsunaga, Toshiyuki;Kawabata, Saori;Ikari, Akira
通讯作者：
Ikari, Akira
溶血磷脂酰胆碱酰基转移酶2介导的脂质液滴生产支持结直肠癌的化学耐药性。
影响因子：
16.6
作者：
Cotte AK;Aires V;Fredon M;Limagne E;Derangère V;Thibaudin M;Humblin E;Scagliarini A;de Barros JP;Hillon P;Ghiringhelli F;Delmas D
通讯作者：
Delmas D