Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.
Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.
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DOI：
10.1038/srep41977
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发表时间：
2017-02-07
影响因子：
4.6
通讯作者：
Shridhar V
中科院分区：
文献类型：
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作者：
Roy D;Mondal S;Khurana A;Jung DB;Hoffmann R;He X;Kalogera E;Dierks T;Hammond E;Dredge K;Shridhar V
有缺陷的自噬和紊乱的代谢途径在癌症中很常见;这两种途径的药理学靶向可以提供可行的治疗选择。然而，这些途径是如何被有限的生长因子调节的仍然是未知的。我们的研究表明，HSulf-1（endosulfatase）是一种已知的肿瘤抑制因子，可减弱硫酸肝素结合生长因子信号传导，也可调节自噬和脂肪生成之间的相互作用。在OV 202和TOV 2223细胞（卵巢癌细胞系）中沉默HSulf-1导致脂滴（LD）增加，自噬空泡（AV）减少和LC 3B斑点减少。相比之下，HSulf-1熟练细胞表现出更多的AV和减少的LD。HSulf-1耗竭细胞中LD增加与ERK介导的cPLA 2S 505磷酸化增加相关。相反，与载体对照相比，SKOV 3细胞中的HSulf-1表达减少了LD的数量并增加了AV的数量。此外，药物（AACOCF 3）和shRNA介导的cPLA 2下调导致LD减少，自噬增加。最后，使用OV 202 Sh 1衍生的异种移植物的体内实验显示AACOCF 3处理有效地减弱肿瘤生长和LD生物发生。总的来说，这些结果显示了在卵巢癌中HSulf-1对自噬和脂质生物合成的相互调节。
Defective autophagy and deranged metabolic pathways are common in cancer; pharmacologic targeting of these two pathways could provide a viable therapeutic option. However, how these pathways are regulated by limited availability of growth factors is still unknown. Our study shows that HSulf-1 (endosulfatase), a known tumor suppressor which attenuates heparin sulfate binding growth factor signaling, also regulates interplay between autophagy and lipogenesis. Silencing of HSulf-1 in OV202 and TOV2223 cells (ovarian cancer cell lines) resulted in increased lipid droplets (LDs), reduced autophagic vacuoles (AVs) and less LC3B puncta. In contrast, HSulf-1 proficient cells exhibit more AVs and reduced LDs. Increased LDs in HSulf-1 depleted cells was associated with increased ERK mediated cPLA2S505 phosphorylation. Conversely, HSulf-1 expression in SKOV3 cells reduced the number of LDs and increased the number of AVs compared to vector controls. Furthermore, pharmacological (AACOCF3) and ShRNA mediated downregulation of cPLA2 resulted in reduced LDs, and increased autophagy. Finally, in vivo experiment using OV202 Sh1 derived xenograft show that AACOCF3 treatment effectively attenuated tumor growth and LD biogenesis. Collectively, these results show a reciprocal regulation of autophagy and lipid biogenesis by HSulf-1 in ovarian cancer.