Department of Biology, Francis Marion University, Florence, SC, USA.
Prostate Cancer Prostatic Dis. 2011 Mar;14(1):30-7. doi: 10.1038/pcan.2010.47. Epub 2010 Nov 30.
Acid ceramidase (AC) overexpression has been observed in prostate cancer cell lines and primary tumors, and contributes to resistance to chemotherapy and radiation. The consequence of AC overexpression is the ability to convert ceramide, which is often produced as a proapoptotic response to stress, to sphingosine, which can then be converted to the prosurvival molecule sphingosine-1-phosphate. In addition to their ability to metabolize ceramide produced in response to stress, we show here that prostate cancer cell lines overexpressing AC also have increased lysosomal density and increased levels of autophagy. Furthermore, pretreatment with 3-methyladenine restores sensitivity of these cells to treatment with C(6) ceramide. We also observed increased expression of the lysosomal stabilizing protein KIF5B and increased sensitivity to the lysosomotropic agent LCL385. Thus, we conclude that AC overexpression increases autophagy in prostate cancer cells, and that increased autophagy enhances resistance to ceramide.
酸性鞘磷脂酶 (AC) 的过表达已在前列腺癌细胞系和原发性肿瘤中观察到，并导致对化疗和放疗的耐药性。AC 过表达的结果是能够将神经酰胺转化为鞘氨醇，神经酰胺通常作为应激的促凋亡反应产生，而鞘氨醇又可以转化为具有生存促进作用的分子 1-磷酸鞘氨醇。除了它们能够代谢应激产生的神经酰胺的能力外，我们在这里还表明，过表达 AC 的前列腺癌细胞系还具有增加的溶酶体密度和增加的自噬水平。此外，用 3-甲基腺嘌呤预处理可恢复这些细胞对 C(6)神经酰胺治疗的敏感性。我们还观察到溶酶体稳定蛋白 KIF5B 的表达增加，并对溶酶体靶向剂 LCL385 更加敏感。因此，我们得出结论，AC 的过表达增加了前列腺癌细胞中的自噬，并且增加的自噬增强了对神经酰胺的耐药性。
