Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA.
Massey Cancer Center, Richmond, VA 23298, USA.
Cells. 2023 Jul 18;12(14):1886. doi: 10.3390/cells12141886.
Glycosphingolipids (GSL) are plasma membrane components that influence molecular processes involved in cancer initiation, progression, and therapeutic responses. They also modulate receptor tyrosine kinases involved in EMT. Therefore, understanding the mechanisms that regulate GSLs in cancer has important therapeutic potential. One critical regulator of GSLs is the lysosomal glucosylceramidase β1 (GBA) that catalyzes the last step in GSL degradation. We show that, in cancer, GBA copy number amplifications and increased expression are widespread. We show that depleting GBA in squamous cell carcinoma cell lines results in a mesenchymal-to-epithelial shift, decreased invasion and migration, increased chemotherapeutic sensitivity, and decreased activation of receptor tyrosine kinases that are involved in regulating EMT. Untargeted lipidomics shows that GBA depletion had significant effects on sphingolipids and GSLs, suggesting that increased GBA activity in cancer sustains EMT and chemoresistance by modulating receptor tyrosine kinase activity and signaling via effects on the cellular lipid profile.
糖鞘脂类 (GSL) 是质膜的组成部分，影响癌症起始、进展和治疗反应中涉及的分子过程。它们还调节参与 EMT 的受体酪氨酸激酶。因此，了解调节癌症中 GSL 的机制具有重要的治疗潜力。糖鞘脂类的一个关键调节剂是溶酶体葡萄糖神经酰胺酶β1 (GBA)，它催化 GSL 降解的最后一步。我们表明，在癌症中，GBA 拷贝数扩增和表达增加是广泛存在的。我们表明，在鳞状细胞癌细胞系中耗尽 GBA 会导致上皮间充质转化，侵袭和迁移减少，化疗敏感性增加，以及参与调节 EMT 的受体酪氨酸激酶的激活减少。非靶向脂质组学表明，GBA 耗竭对鞘脂类和 GSL 有显著影响，这表明增加的 GBA 活性通过影响细胞脂质谱来调节受体酪氨酸激酶活性和信号转导，从而维持 EMT 和化疗耐药性。
