文章：

Tafazzin通过调控ER阳性乳腺癌的细胞磷脂组成介导他莫昔芬耐药

Tafazzin mediates tamoxifen resistance by regulating cellular phospholipid composition in ER-positive breast cancer 

原文发布日期：2023-11-07 

英文摘要：

Tamoxifen is the frontline therapeutic agent for the estrogen receptor-positive (ER + ) subtype of breast cancer patients, which accounts for 70–80% of total breast cancer incidents. However, clinical resistance to tamoxifen has become increasingly common, highlighting the need to identify the underlying cellular mechanisms. In our study, we employed a genome-scale CRISPR-Cas9 loss-of-function screen and validation experiments to discover that Tafazzin (TAZ), a mitochondrial transacylase, is crucial for maintaining the cellular sensitivity of ER+ breast cancer cells to tamoxifen and other chemotherapies. Mechanistically, we found that cardiolipin, whose synthesis and maturation rely on TAZ, is required to maintain cellular sensitivity to tamoxifen. Loss of metabolic enzymatic activity of TAZ causes ERα downregulation and therapy resistance. Interestingly, we observed that TAZ deficiency also led to the upregulation of lysophosphatidylcholine (LPC), which in turn suppressed ERα expression and nuclear localization, thereby contributing to tamoxifen resistance. LPC is further metabolized to lysophosphatidic acid (LPA), a bioactive molecule that supports cell survival. Thus, our findings suggest that the depletion of TAZ promotes tamoxifen resistance through an LPC-LPA phospholipid synthesis axis, and targeting this lipid metabolic pathway could restore cell susceptibility to tamoxifen treatment. 

摘要翻译： 

他莫昔芬是雌激素受体阳性（ER+）亚型乳腺癌患者的一线治疗药物，该亚型占乳腺癌总发病率的70-80%。然而，临床上对他莫昔芬的耐药性日益普遍，这凸显了识别潜在细胞机制的必要性。在我们的研究中，我们采用基因组规模的CRISPR-Cas9功能缺失筛选及验证实验，发现线粒体转酰基酶Tafazzin（TAZ）对维持ER+乳腺癌细胞对他莫昔芬及其他化疗药物的敏感性至关重要。机制上，我们发现心磷脂（其合成和成熟依赖于TAZ）是维持细胞对他莫昔芬敏感性的必要条件。TAZ代谢酶活性的丧失会导致ERα下调及治疗耐药性。有趣的是，我们观察到TAZ缺陷还会引起溶血磷脂酰胆碱（LPC）的上调，进而抑制ERα的表达和核定位，从而导致他莫昔芬耐药。LPC可进一步代谢为具有生物活性的溶血磷脂酸（LPA），这种分子能支持细胞存活。因此，我们的研究结果表明，TAZ的缺失通过LPC-LPA磷脂合成轴促进了他莫昔芬耐药，而靶向该脂质代谢通路可能恢复细胞对他莫昔芬治疗的敏感性。

原文链接：

Tafazzin mediates tamoxifen resistance by regulating cellular phospholipid composition in ER-positive breast cancer