Yu Miao, Chen Qian, Lu Yi-Ping
Department of Surgical Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China.
Clinical School of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China.
World J Gastrointest Oncol. 2024 Jul 15;16(7):3230-3240. doi: 10.4251/wjgo.v16.i7.3230.
Aldehyde (ALDH2) dysfunction has been verified to contribute to human cancers.
To investigate the molecular mechanism and biological function of ALDH2 in colorectal cancer (CRC) progression.
Human CRC cells with high expression of ALDH2 were screened. After shRNA ALDH2 (sh-ALDH2) transfection, phenotypes [proliferation, apoptosis, acetaldehyde (ACE) accumulation, DNA damage] of CRC cells were verified using cell counting kit-8, flow cytometry, ACE assay, and comet assays. Western blotting was used for evaluation of the apoptosis proteins (Bax and Bcl-2) and JNK/p38 MAPK pathway-associated proteins. We subjected CVT-10216 (a selective ALDH2 inhibitor) to nude mice for establishment of SK-CO-1 mouse xenograft model and observed the occurrence of CRC.
The inhibition of ALDH2 could promote the malignant structures of CRC cells, including apoptosis, ACE level, and DNA damage, and cell proliferation was decreased in the sh-ALDH2 group, whereas ALDH2 agonist Alda-1 reversed features. ALDH2 repression can cause ACE accumulation, whereas ACE enhanced CRC cell features related to increased DNA damage. Additionally, ALDH2 repression led to JNK/P38 MAPK activation, and apoptosis, ACE accumulation, and DNA damage were inhibited after p38 MAPK inhibitor SB203580 and JNK inhibitor SP600125 addition. ACE accumulation and raised DNA damage were recognized in CVT-10216 treated-mouse tumor tissues .
The repression of ALDH2 led to ACE accumulation, inducing cell apoptosis and DNA damage by the JNK/p38 MAPK signaling pathway activation in CRC.
醛脱氢酶2（ALDH2）功能障碍已被证实与人类癌症有关。
研究ALDH2在结直肠癌（CRC）进展中的分子机制和生物学功能。
筛选出高表达ALDH2的人CRC细胞。转染shRNA ALDH2（sh-ALDH2）后，使用细胞计数试剂盒-8、流式细胞术、乙醛（ACE）检测和彗星试验验证CRC细胞的表型[增殖、凋亡、ACE积累、DNA损伤]。采用蛋白质免疫印迹法评估凋亡蛋白（Bax和Bcl-2）以及JNK/p38 MAPK信号通路相关蛋白。将CVT-10216（一种选择性ALDH2抑制剂）作用于裸鼠以建立SK-CO-1小鼠异种移植模型，并观察CRC的发生情况。
抑制ALDH2可促进CRC细胞的恶性表型，包括凋亡、ACE水平和DNA损伤，sh-ALDH2组细胞增殖减少，而ALDH2激动剂Alda-1可逆转这些特征。抑制ALDH2可导致ACE积累，而ACE增强了CRC细胞与DNA损伤增加相关的特征。此外，抑制ALDH2导致JNK/P38 MAPK激活，添加p38 MAPK抑制剂SB203580和JNK抑制剂SP600125后，凋亡、ACE积累和DNA损伤受到抑制。在CVT-10216处理的小鼠肿瘤组织中观察到ACE积累和DNA损伤增加。
抑制ALDH2导致ACE积累，通过激活CRC中的JNK/p38 MAPK信号通路诱导细胞凋亡和DNA损伤。
