Wu Wei, Wu Yang, Mayer Karoline, von Rosenstiel Charlotte, Schecker Johannes, Baur Sandra, Würstle Sylvia, Liesche-Starnecker Friederike, Gempt Jens, Schlegel Jürgen
Department of Neuropathology, Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str.22, 81675 München, Germany.
Department of Neurosurgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str.22, 81675 München, Germany.
Transl Oncol. 2020 Mar;13(3):100748. doi: 10.1016/j.tranon.2020.100748. Epub 2020 Feb 19.
Glioblastoma (GBM) is the most malignant primary brain tumor. Relapse occurs regularly, and the clinical behavior seems to be due to a therapy-resistant subpopulation of glioma-initiating cells that belong to the group of cancer stem cells. Aldehyde dehydrogenase (ALDH) has been identified as a marker for this cell population, and we have shown previously that ALDH1A3-positive GBM cells are more resistant against temozolomide (TMZ) treatment. However, it is still unclear how ALDH expression mediates chemoresistance.
ALDH1A3 expression was analyzed in 112 specimens from primary and secondary surgical resections of 56 patients with GBM (WHO grade IV). All patients received combined adjuvant radiochemotherapy. For experimental analysis, CRISPR-Cas9-induced knockout cells from three established GBM cell lines (LN229, U87MG, T98G) and two glioma stem-like cell lines were investigated after TMZ treatment.
ALDH1A3 knockout cells were more sensitive to TMZ, and oxidative stress seemed to be the molecular process where ALDH1A3 exerts its role in resistance against TMZ. Oxidative stress led to lipid peroxidation, yielding active aldehydes that were detoxified by ALDH enzymatic activity. During the metabolic process, autophagy was induced leading to downregulation of the enzyme, but ALDH1A3 is upregulated to even higher expression levels after finishing the TMZ therapy in vitro. Recurrent GBMs show significantly higher ALDH1A3 expression than the respective samples from the primary tumor, and patients suffering from GBM with high ALDH1A3 expression showed a shorter median survival time (12 months vs 21 months, P < .05).
Oxidative stress is an important and clinically relevant component of TMZ-induced therapeutic effects. Cytotoxicity seems to be mediated by aldehydes resulting from lipid peroxidation, and ALDH1A3 is able to reduce the number of toxic aldehydes. Therefore, we present a molecular explanation of the role of ALDH1A3 in therapeutic resistance of human GBM cells.
胶质母细胞瘤（GBM）是最恶性的原发性脑肿瘤。复发经常发生，其临床行为似乎归因于属于癌症干细胞群体的具有治疗抗性的胶质瘤起始细胞亚群。醛脱氢酶（ALDH）已被确定为该细胞群体的标志物，并且我们之前已经表明，ALDH1A3阳性GBM细胞对替莫唑胺（TMZ）治疗更具抗性。然而，ALDH表达如何介导化疗抗性仍不清楚。
分析了56例GBM（世界卫生组织IV级）患者的原发性和二次手术切除的112个标本中的ALDH1A3表达。所有患者均接受了联合辅助放化疗。对于实验分析，在TMZ治疗后研究了来自三种已建立的GBM细胞系（LN229、U87MG、T98G）和两种胶质瘤干细胞样细胞系的CRISPR-Cas9诱导的敲除细胞。
ALDH1A3敲除细胞对TMZ更敏感，氧化应激似乎是ALDH1A3在抗TMZ抗性中发挥作用的分子过程。氧化应激导致脂质过氧化，产生活性醛，这些醛通过ALDH酶活性被解毒。在代谢过程中，自噬被诱导导致该酶的下调，但在体外完成TMZ治疗后，ALDH1A3上调至更高的表达水平。复发性GBM显示出比原发性肿瘤的相应样本显著更高的ALDH1A3表达，并且患有高ALDH1A3表达的GBM患者的中位生存时间较短（12个月对21个月，P<0.05）。
氧化应激是TMZ诱导的治疗效果的重要且临床相关的组成部分。细胞毒性似乎由脂质过氧化产生的醛介导，并且ALDH1A3能够减少有毒醛的数量。因此，我们对ALDH1A3在人GBM细胞治疗抗性中的作用提出了分子解释。
