Aldh1a1, short for aldehyde dehydrogenase 1 family member A1, is an enzyme involved in retinoic acid biosynthesis and redox balance [2]. It can metabolize reactive aldehydes to their corresponding carboxylic acid derivatives and plays important physiological and toxicological roles in areas such as the CNS, metabolic disorders, and cancers [5].

In cancer, Aldh1a1 has been extensively studied. In breast cancer, its enzymatic activity facilitates tumor growth by decreasing intracellular pH, promoting TAK1 phosphorylation, activating NFκB signaling, and increasing GM-CSF secretion, leading to myeloid-derived suppressor cell expansion and immunosuppression [1]. In KRAS-mutated cancers, Aldh1a1 increases in response to KRAS inhibitors, conferring resistance by counteracting ferroptosis. Knockout or inhibition of Aldh1a1 improves the efficacy of KRAS inhibitors in cells, patient-derived organoids, and xenograft models [2]. In prostate cancer, Aldh1a1 positively regulates tumor cell survival in circulation, extravasation, and metastatic dissemination, and its gain in bone metastases is associated with high PLK3 expression [3]. In EGFR-mutant lung cancer, S100A9 upregulates Aldh1a1 expression, activating the retinoic acid signaling pathway in osimertinib-refractory cancer cells, and genetic repression of Aldh1a1 reduces brain metastasis [4]. In glioblastoma, overexpression of Aldh1a1 in U87 cells increases cell growth and invasion, and it promotes AKT phosphorylation [7]. In acute myeloid leukemia, lower RNA expression of Aldh1a1 is associated with a favorable prognosis, while high expression is linked to high risk and poor overall survival [8]. Additionally, targeting Aldh1a1 can inhibit tumor growth and immune escape in various cancers [6].

In conclusion, Aldh1a1 is a key enzyme with significant implications in multiple biological processes and disease conditions, especially in cancer. Studies using knockout or inhibition models have revealed its roles in tumor progression, metastasis, drug resistance, and immune escape, highlighting its potential as a therapeutic target in cancer treatment.

References:

1. Liu, Cuicui, Qiang, Jiankun, Deng, Qiaodan, Zhang, Lixing, Liu, Suling. 2021. ALDH1A1 Activity in Tumor-Initiating Cells Remodels Myeloid-Derived Suppressor Cells to Promote Breast Cancer Progression. In Cancer research, 81, 5919-5934. doi:10.1158/0008-5472.CAN-21-1337. https://pubmed.ncbi.nlm.nih.gov/34580061/

2. Bian, Yunyi, Shan, Guangyao, Bi, Guoshu, Fan, Hong, Zhan, Cheng. 2024. Targeting ALDH1A1 to enhance the efficacy of KRAS-targeted therapy through ferroptosis. In Redox biology, 77, 103361. doi:10.1016/j.redox.2024.103361. https://pubmed.ncbi.nlm.nih.gov/39317105/

3. Gorodetska, Ielizaveta, Offermann, Anne, Püschel, Jakob, Perner, Sven, Dubrovska, Anna. 2024. ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription. In Theranostics, 14, 714-737. doi:10.7150/thno.88057. https://pubmed.ncbi.nlm.nih.gov/38169509/

4. Biswas, Anup Kumar, Han, Seoyoung, Tai, Yifan, Massague, Joan, Acharyya, Swarnali. . Targeting S100A9-ALDH1A1-Retinoic Acid Signaling to Suppress Brain Relapse in EGFR-Mutant Lung Cancer. In Cancer discovery, 12, 1002-1021. doi:10.1158/2159-8290.CD-21-0910. https://pubmed.ncbi.nlm.nih.gov/35078784/

5. Li, Bingyan, Yang, Kang, Liang, Dailin, Jiang, Cheng, Ma, Zonghui. 2020. Discovery and development of selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors. In European journal of medicinal chemistry, 209, 112940. doi:10.1016/j.ejmech.2020.112940. https://pubmed.ncbi.nlm.nih.gov/33328099/

6. Wang, Mingyuan, Wang, Taoli, Wang, Jinjin, Chen, Huan, Liao, Jingnan. 2024. ALDH1A1 promotes immune escape of tumor cells through ZBTB7B-glycolysis pathway. In Cell death & disease, 15, 568. doi:10.1038/s41419-024-06943-9. https://pubmed.ncbi.nlm.nih.gov/39107297/

7. Huang, Yu-Kai, Wang, Tzu-Ming, Chen, Chi-Yu, Pan, Yuan, Chang, Kun-Che. 2024. The role of ALDH1A1 in glioblastoma proliferation and invasion. In Chemico-biological interactions, 402, 111202. doi:10.1016/j.cbi.2024.111202. https://pubmed.ncbi.nlm.nih.gov/39128802/

8. Dancik, Garrett M, Voutsas, Ioannis F, Vlahopoulos, Spiros. 2022. Lower RNA expression of ALDH1A1 distinguishes the favorable risk group in acute myeloid leukemia. In Molecular biology reports, 49, 3321-3331. doi:10.1007/s11033-021-07073-7. https://pubmed.ncbi.nlm.nih.gov/35028852/