Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-B-dependent P-glycoprotein upregulation
Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-B-dependent P-glycoprotein upregulation
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DOI：
10.1194/jlr.m091876
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发表时间：
2019-06-01
影响因子：
6.5
通讯作者：
Loughran, Thomas P.
中科院分区：
文献类型：
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作者：
Tan, Su-Fern;Dunton, Wendy;Loughran, Thomas P.
急性髓系白血病（AML）是成人中最常见的急性白血病。超过一半的老年 AML 患者对细胞毒性化疗没有反应，大多数反应者会出现耐药性疾病复发。未能实现完全缓解的部分原因是 AML 母细胞的耐药优势，这些母细胞经常表达 P-糖蛋白 (P-gp)，一种 ATP 结合盒转运蛋白。我们之前的工作表明，AML 中酸性神经酰胺酶 (AC) 水平升高有助于母细胞存活。在这里，我们研究了 AML 中相对于 AC 的 P-gp 表达水平。使用亲本 HL-60 细胞和耐药衍生物作为我们的模型，我们发现耐药衍生物中 P-gp 表达和外排活性高度上调。 HL-60 中的 AC 过表达赋予对 AML 化疗药物阿糖胞苷、米托蒽醌和柔红霉素的耐药性，并与 P-gp 上调有关。此外，通过药理学或遗传方法靶向AC可降低P-gp水平并增加对化疗药物的敏感性。从机制上讲，AC 过表达增加了 NF-B 激活，而 NF-kB 抑制剂降低了 P-gp 水平，表明 NF-kappaB 途径有助于 AC 介导的 P-gp 表达调节。因此，我们的数据支持 AC 在耐药性和生存中发挥重要作用，并表明鞘脂靶向方法也可能影响 AML 的耐药性。
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. More than half of older AML patients fail to respond to cytotoxic chemotherapy, and most responders relapse with drug-resistant disease. Failure to achieve complete remission can be partly attributed to the drug resistance advantage of AML blasts that frequently express P-glycoprotein (P-gp), an ATP-binding cassette transporter. Our previous work showed that elevated acid ceramidase (AC) levels in AML contribute to blast survival. Here, we investigated P-gp expression levels in AML relative to AC. Using parental HL-60 cells and drug-resistant derivatives as our model, we found that P-gp expression and efflux activity were highly upregulated in resistant derivatives. AC overexpression in HL-60 conferred resistance to the AML chemotherapeutic drugs, cytarabine, mitoxantrone, and daunorubicin, and was linked to P-gp upregulation. Furthermore, targeting AC through pharmacologic or genetic approaches decreased P-gp levels and increased sensitivity to chemotherapeutic drugs. Mechanistically, AC overexpression increased NF-B activation whereas NF-kB inhibitors reduced P-gp levels, indicating that the NF-kappaB pathway contributes to AC-mediated modulation of P-gp expression. Hence, our data support an important role for AC in drug resistance as well as survival and suggest that sphingolipid targeting approaches may also impact drug resistance in AML.