The association of circulating lipids with clinical outcomes of drug-resistant castration-resistant prostate cancer (DR-CRPC) is not fully understood. While it is known that increases in select lipids correlate to decreased survival, neither the mechanisms mediating these alterations nor the correlation of resistance to drug treatments is well characterized. This gap-in-knowledge was addressed using in vitro models of non-cancerous, hormone-sensitive, CRPC and drug-resistant cell lines combined with quantitative LC-ESI-Orbitrap-MS (LC-ESI-MS/MS) lipidomic analysis and subsequent analysis such as Metaboanalyst and Lipid Pathway Enrichment Analysis (LIPEA). Several lipid regulatory pathways were identified that are associated with Docetaxel resistance in prostate cancer (PCa). These included those controlling glycerophospholipid metabolism, sphingolipid signaling and ferroptosis. In total, 7460 features were identified as being dysregulated between the cell lines studied, and 21 lipid species were significantly altered in drug-resistant cell lines as compared to nonresistant cell lines. Docetaxel resistance cells (PC3-Rx and DU145-DR) had higher levels of phosphatidylcholine (PC), oxidized lipid species, phosphatidylethanolamine (PE), and sphingomyelin (SM) as compared to parent control cells (PC-3 and DU-145). Alterations were also identified in the levels of phosphatidic acid (PA) and diacylglyceride (DAG), whose levels are regulated by Lipin (LPIN), a phosphatidic acid phosphatase that converts PA to DAG. Data derived from cBioPortal demonstrated a population of PCa patients expressing mutations aligning with amplification of LPIN1, LPIN2 and LPIN3 genes. Lipin amplification in these genes correlated to decreased survival in these patients. Lipin-1 mRNA expression also showed a similar trend in PCa patient data. Lipin-1, but not Lipin-2 or − 3, was detected in several prostate cancer cells, and was increased in 22RV1 and PC-3 cell lines. The increased expression of Lipin-1 in these cells correlated with the level of PA. These data identify lipids whose levels may correlate to Docetaxel sensitivity and progression of PCa. The data also suggest a correlation between the expression of Lipin-1 in cells and patients with regards to prostate cancer cell aggressiveness and patient survivability. Ultimately, these data may be useful for identifying markers of lethal and/or metastatic prostate cancer.

中文翻译：

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鉴定与耐药前列腺癌细胞相关的脂质组学特征


循环脂质与耐药去势抵抗性前列腺癌 (DR-CRPC) 临床结果的关联尚不完全清楚。虽然众所周知，特定脂质的增加与生存率降低相关，但介导这些改变的机制和药物治疗耐药性的相关性都没有得到很好的表征。使用非癌性、激素敏感性、CRPC 和耐药细胞系的体外模型结合定量 LC-ESI-Orbitrap-MS (LC-ESI-MS/MS) 脂质组学分析和后续分析，例如代谢分析和脂质途径富集分析 (LIPEA)。确定了与前列腺癌（PCa）中多西紫杉醇耐药性相关的几种脂质调节途径。这些包括控制甘油磷脂代谢、鞘脂信号传导和铁死亡的那些。总共，7460 个特征被确定为所研究的细胞系之间失调，并且与非耐药细胞系相比，耐药细胞系中的 21 种脂质种类发生了显着改变。与亲代对照细胞（PC-3 和 DU-145）相比，多西紫杉醇耐药细胞（PC3-Rx 和 DU145-DR）具有更高水平的磷脂酰胆碱（PC）、氧化脂质、磷脂酰乙醇胺（PE）和鞘磷脂（SM） 。磷脂酸 (PA) 和二酰甘油 (DAG) 的水平也发生了变化，其水平受到脂质 (LPIN) 的调节，脂质是一种将 PA 转化为 DAG 的磷脂酸磷酸酶。来自 cBioPortal 的数据表明，PCa 患者群体表达与 LPIN1、LPIN2 和 LPIN3 基因扩增一致的突变。这些基因中的脂质扩增与这些患者的生存率降低相关。 PCa 患者数据中 Lipin-1 mRNA 表达也显示出类似的趋势。在几种前列腺癌细胞中检测到 Lipin-1，但未检测到 Lipin-2 或 - 3，并且在 22RV1 和 PC-3 细胞系中含量增加。这些细胞中 Lipin-1 表达的增加与 PA 水平相关。这些数据确定了脂质的水平可能与多西紫杉醇敏感性和 PCa 进展相关。数据还表明细胞和患者中 Lipin-1 的表达与前列腺癌细胞的侵袭性和患者的生存能力之间存在相关性。最终，这些数据可能有助于识别致死性和/或转移性前列腺癌的标志物。