Deswal Bhawna, Nallanthighal Sameera, Nikpayam Elahe, Minhas Zenab, Paul Antoni, Goo Young-Hwa, Cheon Dong-Joo
Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, USA.
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
Oncogenesis. 2025 Jul 2;14(1):22. doi: 10.1038/s41389-025-00566-1.
Lipid droplet-associated hydrolase (LDAH) is a lipid hydrolase abundantly expressed in adipose and ovarian tissues and macrophages. However, LDAH's functions in ovarian cancer are largely unknown. Analysis of publicly available patient datasets showed decreased LDAH expression in advanced stages of ovarian cancer, and low LDAH levels were associated with poor survival outcomes in ovarian cancer patients. Consistently, knockdown (KD) of LDAH in human ovarian cancer cell lines increased tumor cell proliferation but decreased endoplasmic reticulum (ER) stress and apoptosis upon cisplatin treatment. In addition, compared to scrambled control, LDAH KD ovarian cancer cells showed smaller lipid droplets (LDs), decreased triacylglycerol (TAG) content, and increased expression of adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1 A (CPT1A), and phospho-NF-kB. Our xenograft studies also showed increased tumor growth, increased ATGL expression, and decreased apoptosis after cisplatin treatment in LDAH KD tumors. ATGL overexpression increased cisplatin resistance and expression of CPT1A and phospho-NF-kB, whereas treatment of LDAH KD cells with an ATGL inhibitor attenuated the phenotype. Lastly, we observed that high ATGL levels were associated with shorter survival in ovarian cancer patients. Collectively, our results suggest that ovarian cancer cells downregulate LDAH expression, leading to enhanced ATGL-mediated TAG hydrolysis and increased tumor growth and chemoresistance.
脂滴相关水解酶（LDAH）是一种在脂肪组织、卵巢组织和巨噬细胞中大量表达的脂水解酶。然而，LDAH在卵巢癌中的功能在很大程度上尚不清楚。对公开可用的患者数据集进行分析发现，在卵巢癌晚期LDAH表达降低，且LDAH水平低与卵巢癌患者的不良生存结果相关。同样，在人卵巢癌细胞系中敲低（KD）LDAH可增加肿瘤细胞增殖，但在顺铂治疗后可降低内质网（ER）应激和细胞凋亡。此外，与乱序对照相比，LDAH敲低的卵巢癌细胞显示脂滴（LD）较小、三酰甘油（TAG）含量降低，且脂肪甘油三酯脂肪酶（ATGL）、肉碱棕榈酰转移酶1A（CPT1A）和磷酸化核因子κB（phospho-NF-κB）的表达增加。我们的异种移植研究还显示，在LDAH敲低的肿瘤中，顺铂治疗后肿瘤生长增加、ATGL表达增加且细胞凋亡减少。ATGL过表达增加了顺铂耐药性以及CPT1A和磷酸化核因子κB的表达，而用ATGL抑制剂处理LDAH敲低的细胞可减弱该表型。最后，我们观察到卵巢癌患者中高ATGL水平与较短生存期相关。总体而言，我们的结果表明卵巢癌细胞下调LDAH表达，导致ATGL介导的TAG水解增强，进而增加肿瘤生长和化疗耐药性。
