An aldehyde dehydrogenase 1A3 inhibitor attenuates the metastasis of human colorectal cancer.

Autor: Duan JJ; Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China., Wang D; Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China., Cai J; Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China., Chen JJ; Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China., Zheng XX; Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China., Chen TQ; Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; School of Pharmacy, Shanxi Medical University, Taiyuan, 030002, Shanxi, China., Wang J; Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China., Zhang X; Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China., Yang QK; Institute of Cancer Stem Cell, Cancer Center, Second Affiliated Hospital, Dalian Medical University, Dalian, 116044, China. Electronic address: yangqingkai@dmu.edu.cn., Yu SC; Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. Electronic address: yushicang@163.com.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2022 Jun 28; Vol. 536, pp. 215662. Date of Electronic Publication: 2022 Mar 22.
DOI: 10.1016/j.canlet.2022.215662
Abstrakt: Metastasis is the leading cause of death for patients with colorectal cancer (CRC). The development of therapeutic regimens that selectively inhibit the biological processes involved in CRC cell dissemination is important. We used multiple Affymetrix DNA microarray hybridization datasets to identify genes related to metastasis and have significant prognostic value for patients with CRC. Quantitative real-time PCR, immunofluorescent and immunohistochemical staining were used to evaluate mRNA and protein expression. The function of aldehyde dehydrogenase 1A3 (ALDH1A3) in invasion was assessed by performing transwell assays and animal experiments. Real-time PCR, luciferase reporter assays, and western blotting were used to identify the genes regulated by ALDH1A3. Molecular docking, MTS assays, cellular thermal shift assays, isothermal titration calorimetry, microscale thermophoresis, and enzymatic activity assays were used to screen and verify the efficacy of the ALDH1A3-specific inhibitor YD1701 (dibenzo-30-crown10-ether). Finally, subcutaneous or orthotopic xenograft models were established to investigate the therapeutic potential of YD1701. Human ALDH1A3 was identified to correlate with a metastatic phenotype in CRC cells and a poor patient prognosis. Moreover, ALDH1A3 upregulated the expression of ZEB1 and SNAI2 by inhibiting miR-200 family members. The ALDH1A3-specific inhibitor YD1701 was screened, attenuated the invasion of CRC cells in vitro, and prolonged the survival of mice bearing subcutaneous or orthotopic xenografts. Our results show that ALDH1A3 promotes invasion and metastasis via the miR-200-ZEB1/SANI2 axis and is thus a plausible marker for predicting CRC progression. Inhibiting ALDH1A3 with the identified compound YD1701 might represent an effective therapeutic approach to prevent the metastasis of CRC.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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