The stem cell/cancer stem cell marker ALDH1A3 regulates the expression of the survival factor tissue transglutaminase, in mesenchymal glioma stem cells.
The stem cell/cancer stem cell marker ALDH1A3 regulates the expression of the survival factor tissue transglutaminase, in mesenchymal glioma stem cells.
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DOI：
10.18632/oncotarget.16479
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发表时间：
2017-04-04
期刊：
影响因子：
--
通讯作者：
Wilson KF
中科院分区：
文献类型：
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作者：
Sullivan KE;Rojas K;Cerione RA;Nakano I;Wilson KF
组织转谷氨酰胺酶 (tTG) 是一种具有 GTP 结合和酰基转移酶活性的双功能酶，与侵袭性癌细胞和癌症干细胞（包括神经胶质瘤干细胞 (GSC)）的存活和化疗耐药性有关。使用包含两种不同 GSC 亚型（称为原神经 (PN) 和间充质 (MES)）的模型系统，我们发现表型侵袭性和放射治疗耐药性 MES GSC 相对于 PN GSC 只表达 tTG。因此，这些细胞的自我更新、增殖和存活对 tTG 抑制剂治疗敏感，与高级别神经胶质瘤的标准治疗（即放射或替莫唑胺）相结合时观察到益处。了解 MES GSC 中 tTG 表达的分子驱动因素的努力揭示了 tTG 与干细胞和癌症干细胞的常见标记物醛脱氢酶 1A3 (ALDH1A3) 之间存在意想不到的联系。 ALDH1A3 以及 ALDH1 亚家族的其他成员可以在细胞中充当视黄醛脱氢酶，从视黄醛生成视黄酸 (RA)。我们表明，ALDH1A3 及其产物 RA 的酶活性对于在 MES GSC 中观察到的 tTG 表达是必需的。此外，PN GSC 中 ALDH1A3 的异位表达足以诱导这些细胞中 tTG 的表达，进一步证明了 ALDH1A3 和 tTG 之间的因果关系。总之，这些发现归因于 ALDH1A3 通过上调 tTG 在侵袭性 GSC 表型中发挥新功能，并表明 ALDH1 家族成员在跨癌症类型中具有类似作用的潜力。
Tissue transglutaminase (tTG), a dual-function enzyme with GTP-binding and acyltransferase activities, has been implicated in the survival and chemotherapy resistance of aggressive cancer cells and cancer stem cells, including glioma stem cells (GSCs). Using a model system comprising two distinct subtypes of GSCs referred to as proneural (PN) and mesenchymal (MES), we find that the phenotypically aggressive and radiation therapy-resistant MES GSCs exclusively express tTG relative to PN GSCs. As such, the self-renewal, proliferation, and survival of these cells was sensitive to treatment with tTG inhibitors, with a benefit being observed when combined with the standard of care for high grade gliomas (i.e. radiation or temozolomide). Efforts to understand the molecular drivers of tTG expression in MES GSCs revealed an unexpected link between tTG and a common marker for stem cells and cancer stem cells, Aldehyde dehydrogenase 1A3 (ALDH1A3). ALDH1A3, as well as other members of the ALDH1 subfamily, can function in cells as a retinaldehyde dehydrogenase to generate retinoic acid (RA) from retinal. We show that the enzymatic activity of ALDH1A3 and its product, RA, are necessary for the observed expression of tTG in MES GSCs. Additionally, the ectopic expression of ALDH1A3 in PN GSCs is sufficient to induce the expression of tTG in these cells, further demonstrating a causal link between ALDH1A3 and tTG. Together, these findings ascribe a novel function for ALDH1A3 in an aggressive GSC phenotype via the up-regulation of tTG, and suggest the potential for a similar role by ALDH1 family members across cancer types.