Study on the Role and Related Mechanism of ALDH1B1 in the Development of Colorectal Cancer

Chi Gao; Jianwei Qiao; Weijie Li; Zhihui Tai

doi:10.71204/50ww5z23

Authors

Chi Gao Affiliated Hospital of North China University of Science and Technology Author
Jianwei Qiao Affiliated Hospital of North China University of Science and Technology Author
Weijie Li Affiliated Hospital of North China University of Science and Technology Author
Zhihui Tai Affiliated Hospital of North China University of Science and Technology Author

DOI:

https://doi.org/10.71204/50ww5z23

Keywords:

ALDH1B1, Cancer Stem Cells, Wnt/β- Catenin, Notch Signaling Pathways, Metabolic Reprogramming, Malignant Tumors, Colorectal Cancer

Abstract

Aldehyde dehydrogenases (ALDHs) comprise a broad superfamily of metabolic enzymes, with 19 gene groups identified in the human genome. These genes participate in diverse biological processes, including the detoxification of exogenous and endogenous aldehydes. In recent years, ALDHs have garnered increasing attention due to their association with stem cell-related characteristics in a wide range of hematopoietic malignancies and solid tumors. ALDH1B1, an isoform and member of the ALDH superfamily, is aberrantly expressed in multiple cancers. For instance, ALDH1B1 is dysregulated in pancreatic cancer (particularly pancreatic ductal adenocarcinoma, PDAC), where it drives tumor progression through multiple mechanisms: maintaining stemness (e.g., activating Notch and Wnt/β-catenin pathways), metabolic reprogramming (acetaldehyde metabolism, reducing toxic aldehyde accumulation while generating NADPH to sustain redox balance), activating oncogenic pathways (e.g., inducing WNT signaling to promote epithelial-mesenchymal transition and enhance invasiveness), and conferring therapy resistance. ALDH1B1 overexpression induces significant changes in cell morphology, proliferation rates, and clonogenic efficiency, thereby contributing to lung adenocarcinoma development. In esophageal carcinogenesis, three genome-wide significant loci in heterozygotes include ALDH1B1, which exhibits a genome-wide significant interaction with rs671, potentially increasing the risk of esophageal cancer (a classic alcohol-associated disease). Domestic studies have shown that miR-761 can target and suppress ALDH1B1 to inhibit osteosarcoma cell proliferation, migration, and invasion. Furthermore, ALDH1B1 promotes colorectal cancer progression by regulating cancer stemness and key oncogenic signaling pathways. This article elucidates the mechanistic roles of ALDH1B1 in various malignancies, with a particular focus on its specific interactions in the development and progression of colorectal cancer. Notably, ALDH1B1 promotes colorectal carcinogenesis by mediating unique metabolic reprogramming processes. On one hand, ALDH1B1 maintains intracellular redox balance through acetaldehyde oxidation, creating a favorable metabolic microenvironment for cancer stem cells. On the other hand, its involvement in retinoic acid metabolism dysregulation aberrantly activates key oncogenic pathways such as Wnt/β-catenin signaling. Furthermore, ALDH1B1 enhances the glycolytic switch (the Warburg effect) by modulating mitochondrial energy metabolism, thereby supplying the bioenergetic and biosynthetic precursors required for rapid tumor cell proliferation. These metabolic regulatory mechanisms synergize with ALDH1B1’s role in sustaining cancer stem cell properties, collectively forming a multidimensional network through which ALDH1B1 drives colorectal cancer progression. A deeper understanding of the logical relationship between ALDH1B1-mediated metabolic regulation and carcinogenesis will provide a more comprehensive insight into its role in various cancers, particularly colorectal cancer, and offer a theoretical foundation for developing novel ALDH1B1-targeted therapeutic strategies. However, more detailed molecular mechanisms, clinical relevance, and potential therapeutic value require further experimental and clinical validation.

References

Abu-Serie, M. M., Osuka, S., Heikal, L. A., Teleb, M., Barakat, A., & Dudeja, V. (2024). Diethyldithiocarbamate-ferrous oxide nanoparticles inhibit human and mouse glioblastoma stemness: aldehyde dehydrogenase 1A1 suppression and ferroptosis induction. Front Pharmacol, 15, 1363511.

Alves, A. L. V., Gomes, I. N. F., Carloni, A. C., Rosa, M. N., da Silva, L. S., Evangelista, A. F., Reis, R. M., & Silva, V. A. O. (2021). Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives. Stem Cell Res Ther, 12(1), 206.

Baek, S. H., & Jang, Y. K. (2021). AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination. Int J Mol Sci, 22(21), 12079.

Chen, X., Huang, J., Yu, C., Liu, J., Gao, W., Li, J., Song, X., Zhou, Z., Li, C., Xie, Y., Kroemer, G., Liu, J., Tang, D., & Kang, R. (2022). A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis. Nat Commun, 13(1), 6318.

Cheng, X., Xu, J., Gu, H., Chen, G., & Wu, L. (2024). ALDH1+ tumor stem cells promote the progression of malignant fibrous tissue sarcoma by inhibiting SYNPO2 through hsa-mir-206. Exp Cell Res, 441(1), 114167.

Colicelli, J. (2004). Human RAS superfamily proteins and related GTPases. Sci STKE, 2004(250), 13.

Colotta, F., Allavena, P., Sica, A., Garlanda, C., & Mantovani, A. (2009). Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis, 30(7), 1073-1081.

Crunkhorn, S. (2022). Targeting ALDH1B1 in colorectal cancer. Nat Rev Drug Discov, 21(9), 636.

Daniels, D. L., & Weis, W. I. (2005). Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nat Struct Mol Biol, 12(4), 364-371.

de Aberasturi, A. L., Redrado, M., Villalba, M., Larzabal, L., Pajares, M. J., Garcia, J., Evans, S. R., Garcia-Ros, D., Bodegas, M. E., Lopez, L., Montuenga, L., & Calvo, A. (2016). TMPRSS4 induces cancer stem cell-like properties in lung cancer cells and correlates with ALDH expression in NSCLC patients. Cancer Lett, 370(2), 165-176.

Feng, Z., Hom, M. E., Bearrood, T. E., Rosenthal, Z. C., Fernández, D., Ondrus, A. E., Gu, Y., McCormick, A. K., Tomaske, M. G., Marshall, C. R., Kline, T., Chen, C. H., Mochly-Rosen, D., Kuo, C. J., & Chen, J. K. (2022). Targeting colorectal cancer with small-molecule inhibitors of ALDH1B1. Nat Chem Biol, 18(10), 1065-1075.

Fernando, W., Cruickshank, B. M., Arun, R. P., MacLean, M. R., Cahill, H. F., Morales-Quintanilla, F., Dean, C. A., Wasson, M. D., Dahn, M. L., Coyle, K. M., Walker, O. L., Power Coombs, M. R., & Marcato, P. (2024). ALDH1A3 is the switch that determines the balance of ALDH(+) and CD24(-)CD44(+) cancer stem cells, EMT-MET, and glucose metabolism in breast cancer. Oncogene, 43, 3151-3169.

Ghiringhelli, F., & Fumet, J. D. (2019). Is There a Place for Immunotherapy for Metastatic Microsatellite Stable Colorectal Cancer? Front Immunol, 10, 1816.

Golla, J. P., Kandyliari, A., Tan, W. Y., Chen, Y., Orlicky, D. J., Thompson, D. C., Shah, Y. M., & Vasiliou, V. (2020). Interplay between APC and ALDH1B1 in a newly developed mouse model of colorectal cancer. Chem Biol Interact, 331, 109274.

Gupta, R., Bhatt, L. K., Johnston, T. P., & Prabhavalkar, K. S. (2019). Colon cancer stem cells: Potential target for the treatment of colorectal cancer. Cancer Biol Ther, 20(8), 1068-1082.

Hwang, C. C., Nieh, S., Lai, C. H., Tsai, C. S., Chang, L. C., Hua, C. C., Chi, W. Y., Chien, H. P., Wang, C. W., Chan, S. C., Hsieh, T. Y., & Chen, J. R. (2014). A retrospective review of the prognostic value of ALDH-1, Bmi-1 and Nanog stem cell markers in esophageal squamous cell carcinoma. PLoS One, 9(8), e105676.

Jelski, W., Kozlowski, M., Laudanski, J., Niklinski, J., & Szmitkowski, M. (2009a). The activity of class I, II, III, and IV alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) in esophageal cancer. Dig Dis Sci, 54(4), 725-730.

Jelski, W., Kozlowski, M., Laudanski, J., Niklinski, J., & Szmitkowski, M. (2009b). Alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase activity in the sera of patients with esophageal cancer. Clin Exp Med, 9(2), 131-137.

Lang, D., & Ciombor, K. K. (2022). Diagnosis and Management of Rectal Cancer in Patients Younger Than 50 Years: Rising Global Incidence and Unique Challenges. J Natl Compr Canc Netw, 20(10), 1169-1175.

Langan, R. C., Mullinax, J. E., Ray, S., Raiji, M. T., Schaub, N., Xin, H. W., Koizumi, T., Steinberg, S. M., Anderson, A., Wiegand, G., Butcher, D., Anver, M., Bilchik, A. J., Stojadinovic, A., Rudloff, U., & Avital, I. (2012). A Pilot Study Assessing the Potential Role of non-CD133 Colorectal Cancer Stem Cells as Biomarkers. J Cancer, 3, 231-240.

Lavudi, K., Nuguri, S. M., Pandey, P., Kokkanti, R. R., & Wang, Q. E. (2024). ALDH and cancer stem cells: Pathways, challenges, and future directions in targeted therapy. Life Sci, 356, 123033.

Marcato, P., Dean, C. A., Liu, R. Z., Coyle, K. M., Bydoun, M., Wallace, M., Clements, D., Turner, C., Mathenge, E. G., Gujar, S. A., Giacomantonio, C. A., Mackey, J. R., Godbout, R., & Lee, P. W. (2015). Aldehyde dehydrogenase 1A3 influences breast cancer progression via differential retinoic acid signaling. Mol Oncol, 9(1), 17-31.

Muzio, G., Maggiora, M., Paiuzzi, E., Oraldi, M., & Canuto, R. A. (2012). Aldehyde dehydrogenases and cell proliferation. Free Radic Biol Med, 52(4), 735-746.

Negri, F., Bottarelli, L., de'Angelis, G. L., & Gnetti, L. (2022). KRAS: A Druggable Target in Colon Cancer Patients. Int J Mol Sci, 23(8), 4120.

Qiu, C., Shi, W., Wu, H., Zou, S., Li, J., Wang, D., Liu, G., Song, Z., Xu, X., Hu, J., & Geng, H. (2021). Identification of Molecular Subtypes and a Prognostic Signature Based on Inflammation-Related Genes in Colon Adenocarcinoma. Front Immunol, 12, 769685.

Read, E., Milford, J., Zhu, J., Wu, L., Bilodeau, M., & Yang, G. (2021). The interaction of disulfiram and H(2)S metabolism in inhibition of aldehyde dehydrogenase activity and liver cancer cell growth. Toxicol Appl Pharmacol, 426, 115642.

Reya, T., & Clevers, H. (2005). Wnt signalling in stem cells and cancer. Nature, 434(7035), 843-850.

Singh, S., Arcaroli, J., Chen, Y., Thompson, D. C., Messersmith, W., Jimeno, A., & Vasiliou, V. (2015). ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt/β-Catenin, Notch and PI3K/Akt Signaling Pathways. PLoS One, 10(5), e0121648.

Singh, S., Chen, Y., Matsumoto, A., Orlicky, D. J., Dong, H., Thompson, D. C., & Vasiliou, V. (2015). ALDH1B1 links alcohol consumption and diabetes. Biochem Biophys Res Commun, 463(4), 768-773.

Sun, N., Cai, Q., Zhang, Y., Zhang, R. R., Jiang, J., Yang, H., Qin, C. F., & Cheng, G. (2024). The aldehyde dehydrogenase ALDH1B1 exerts antiviral effects through the aggregation of the adaptor MAVS. Sci Signal, 17(818), eadf8016.

Takebe, N., Miele, L., Harris, P. J., Jeong, W., Bando, H., Kahn, M., Yang, S. X., & Ivy, S. P. (2015). Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol, 12(8), 445-464.

Tang, X., Zuo, C., Fang, P., Liu, G., Qiu, Y., Huang, Y., & Tang, R. (2021). Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy. Front Oncol, 11, 701291.

Toledo-Guzmán, M. E., Hernández, M. I., Gómez-Gallegos Á, A., & Ortiz-Sánchez, E. (2019). ALDH as a Stem Cell Marker in Solid Tumors. Curr Stem Cell Res Ther, 14(5), 375-388.

Tran, T. O., Vo, T. H., Lam, L. H. T., & Le, N. Q. K. (2023). ALDH2 as a potential stem cell-related biomarker in lung adenocarcinoma: Comprehensive multi-omics analysis. Comput Struct Biotechnol J, 21, 1921-1929.

Tsochantaridis, I., Kontopoulos, A., Voulgaridou, G. P., Tsifintaris, M., Triantafyllou, C., & Pappa, A. (2022). Aldehyde Dehydrogenase 1B1 Is Implicated in DNA Damage Response in Human Colorectal Adenocarcinoma. Cells, 11(13), 2017 .

Tsochantaridis, I., Roupas, A., Voulgaridou, G. P., Giatromanolaki, A., Koukourakis, M. I., Panayiotidis, M. I., & Pappa, A. (2021). Aldehyde Dehydrogenase 1B1 Is Associated with Altered Cell Morphology, Proliferation, Migration and Chemosensitivity in Human Colorectal Adenocarcinoma Cells. Biomedicines, 9(1), 44.

Wang, H., Zhang, B., Li, X., Zhou, D., Li, Y., Jia, S., Qi, S., Xu, A., Zhao, X., Wang, J., Bai, Z., Cao, B., Li, N., Dai, M., Chen, H., & Huang, J. (2020). Identification and Validation of Novel Serum Autoantibody Biomarkers for Early Detection of Colorectal Cancer and Advanced Adenoma. Front Oncol, 10, 1081.

Wang, L., Li, S., Luo, H., Lu, Q., & Yu, S. (2022). PCSK9 promotes the progression and metastasis of colon cancer cells through regulation of EMT and PI3K/AKT signaling in tumor cells and phenotypic polarization of macrophages. J Exp Clin Cancer Res, 41(1), 303.

Wang, X. (2022). MicroRNA-761 inhibits osteosarcoma progress by targetingALDH1B1 [Doctor, https://link.cnki.net/doi/10.27466/d.cnki.gzzdu.2022.002914

Wang, Y., Popovic, Z., Charkoftaki, G., Garcia-Milian, R., Lam, T. T., Thompson, D. C., Chen, Y., & Vasiliou, V. (2023). Multi-omics profiling reveals cellular pathways and functions regulated by ALDH1B1 in colon cancer cells. Chem Biol Interact, 384, 110714.

Wood, J. C., Cohen, A. R., Pressel, S. L., Aygun, B., Imran, H., Luchtman-Jones, L., Thompson, A. A., Fuh, B., Schultz, W. H., Davis, B. R., & Ware, R. E. (2016). Organ iron accumulation in chronically transfused children with sickle cell anaemia: baseline results from the TWiTCH trial. Br J Haematol, 172(1), 122-130.

Xie, Y., Hou, W., Song, X., Yu, Y., Huang, J., Sun, X., Kang, R., & Tang, D. (2016). Ferroptosis: process and function. Cell Death Differ, 23(3), 369-379.

Yao, S., Chen, W., Zuo, H., Bi, Z., Zhang, X., Pang, L., Jing, Y., Yin, X., & Cheng, H. (2022). Comprehensive Analysis of Aldehyde Dehydrogenases (ALDHs) and Its Significant Role in Hepatocellular Carcinoma. Biochem Genet, 60(4), 1274-1297.

Yuan, X., Wu, H., Xu, H., Xiong, H., Chu, Q., Yu, S., Wu, G. S., & Wu, K. (2015). Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett, 369(1), 20-27.

Zhao, R., Guo, Z., Lu, K., Chen, Q., Riaz, F., Zhou, Y., Yang, L., Cheng, X., Wu, L., Cheng, K., Feng, L., Liu, S., Wu, X., Zheng, M., Yin, C., & Li, D. (2024). Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression. Cell Death Dis, 15(10), 770.