乙醛脱氢酶1A3(ALDH1A3),醛脱氢酶1A亚家族的三个成员之一,与各种类型实体瘤的进展和耐药性增加有关。最近,据报道,高ALDH1A3表达是恶性胸膜间皮瘤(MPM)患者生存不良的预后,石棉相关的化学耐药癌症.我们处理了MPM细胞,培养为多细胞球体,NR6是一种有效且高度选择性的ALDH1A3抑制剂。在这里,我们报道NR6处理导致有毒醛的积累,诱导DNA损伤,CDKN2A表达和细胞生长停滞。我们观察到,在CDKN2A细胞中,NR6处理诱导IL6表达,但是取消了CXCL8的表达和IL-8的释放,防止中性粒细胞募集和中性粒细胞胞外陷阱(NETs)的产生。此外,我们证明了对ALDH1A3抑制的反应,CDKN2A丢失使细胞命运从衰老转向凋亡。剖析ALDH1A3同工型在MPM细胞和肿瘤微环境中的作用可以为这种癌症的治疗开辟新的前沿。
Aldehyde dehydrogenase 1A3 (
ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high
ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a potent and highly selective
ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, CDKN2A expression and cell growth arrest. We observed that, in CDKN2A proficient cells, NR6 treatment induced IL6 expression, but abolished CXCL8 expression and IL-8 release, preventing both neutrophil recruitment and generation of neutrophil extracellular traps (NETs). Furthermore, we demonstrate that in response to
ALDH1A3 inhibition, CDKN2A loss skewed cell fate from senescence to apoptosis. Dissecting the role of
ALDH1A3 isoform in MPM cells and tumour microenvironment can open new fronts in the treatment of this cancer.