Aldehyde Dehydrogenase 2 Family Member (ALDH2) Is a Therapeutic Index for Oxaliplatin Response on Colorectal Cancer Therapy with Dysfunction p53

Abstract

Oxaliplatin resistance is a major issue in the treatment of p53 mutant colorectal cancer (CRC). Finding the specific biomarkers would improve therapeutic efficacy of patients with CRC. In order to figure out the biomarker for CRC patients with mutant p53 access oxaliplatin, a Gene Expression Omnibus dataset (GSE42387) was used to determine differentially expressed genes (DEGs). The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software were used to predict protein-protein interactions. The Database for Annotation, Visualization, and Integrated Discovery online tool was used to group the DEGs into their common pathways. 138 DEGs were identified with 46 upregulated and 92 downregulated. In the PPI networks, 7 of the upregulated genes and 13 of the downregulated genes were identified as hub genes (high degrees). Four hub genes, aldehyde dehydrogenase 2 family member (ALDH2), aldo-keto reductase family 1 member B1 (AKR1B1), aldo-keto reductase family 1 member B10 (AKR1B10), and monoglyceride lipase (MGLL) were enriched in the most significant pathway, glycerolipid metabolism. Further, we found that low expression of ALDH2 is correlated with poor overall survival and oxaliplatin resistance. Finally, we found that combined treatment with ALDH2 inhibitor and oxaliplatin will reduce the sensitivity to oxaliplatin in p53 mutant HT29 cells. In conclusion, we demonstrate that ALDH2 may be a biomarker for oxaliplatin resistance status in CRC patients and bring new insight into treatment strategy for p53 mutant CRC patients.

ALDH2 promotes cancer stemness and metastasis in colorectal cancer through activating β‐catenin signaling

“…Previously, we reported that ALDH2, the critical enzyme in the oxidative pathway in alcohol metabolism, is correlated with chemotherapeutic drug resistance. However, the low expression level of ALDH2 was associated with poor patient survival, and inhibiting ADH2 by daidzein increased oxaliplatin resistance in the CRC cell line with p53 mutation, HT29, but not in p53 wild‐type cell line, HCT 116 22 . In this study, we focused on the role of ALDH2 in CRC progression by inhibiting the enzymatic activity of ALDH2 by CVT‐116 and daidzein.…”

“…However, the low expression level of ALDH2 was associated with poor patient survival, and inhibiting ADH2 by daidzein increased oxaliplatin resistance in the CRC cell line with p53 mutation, HT29, but not in p53 wild-type cell line, HCT 116. 22 In this study, we focused on the role of ALDH2 in CRC progression by inhibiting the enzymatic activity of ALDH2 by CVT-116 and daidzein. Our results demonstrated that inhibiting ALDH2 by CVT-10216 significantly reduced HCT 116 and DLD-1 colon cancer cell migration and stemness.…”

“…Moreover, ALDH2 also drives cancer stemness. It modulates liver cancer stem cell formation (LSCs), and previously, we reported that ALDH2 could be a biomarker for oxaliplatin resistance in p53 mutant CRC 22,23 . However, the role of ALDH2 in regulating CRC progression remains unclear.…”

Preclinical In Silico Evidence Indicates the Pharmacological Targets and Mechanisms of Mogroside V in Patients With Ovarian Cancer and Coronavirus Disease 2019

“…Mogroside V anti-COVID-19/ovarian cancer action targets were obtained from the STRING ( 21 ) database to establish target–target function-related protein interactions with a minimum reciprocal value of 0.09. The results were imported into Cytoscape_v3.6.1 ( 22 ) to construct the mogroside V anti-COVID-19/ovarian cancer target-related protein–protein interaction (PPI) network.…”