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

Abstract

Colorectal cancer (CRC) is the primary cause of death from gastrointestinal cancers. Aldehyde dehydrogenase 2 (ALDH2), a crucial mitochondrial enzyme for the oxidative pathway of alcohol metabolism, plays a dual role in cancer progression. In some cancers, it is tumor suppressive; in others, it drives cancer progression. However, whether targeting ALDH2 has any therapeutic implications or prognostic value in CRC is still unclear. Here, we investigated the role of ALDH2 in CRC progression by targeting its enzymatic activity rather than gene expression. We found that inhibiting ALDH2 by CVT‐10216 and daidzein significantly decrease migration and stemness properties of both DLD‐1 and HCT 116 cells, whereas activating ALDH2 by Alda‐1 enhances migration rate. Concomitantly, ALDH2 inhibition by both CVT‐10216 and daidzein downregulates the mRNA levels of fibronectin, snail, twist, MMP7, CD44, c‐Myc, SOX2, and OCT‐4, which are oncogenic in the advanced stage of CRC. Furthermore, Gene Set Enrichment Analysis (GSEA) on ALDH2 co‐expressed genes from The Cancer Genome Atlas (TCGA) revealed that MYC target gene sets are upregulated. We found that ALDH2 inhibition decreased the nuclear protein levels of pGSK3β serine 9 and c‐Myc. This suggests that ALDH2 probably targets β‐catenin signaling in CRC cells. Together, our results demonstrate the prognostic value of ALDH2 in CRC as it regulates both CRC stemness and migration. Our findings also propose that the plant‐derived isoflavone daidzein could be a potential chemotherapeutic drug targeting ALDH2 in CRC.

PCTAIRE Protein Kinase 1 (PCTK1) Suppresses Proliferation, Stemness, and Chemoresistance in Colorectal Cancer through the BMPR1B-Smad1/5/8 Signaling Pathway

“…The Bio-Rad Protein Assay Kit (Bio-Rad Laboratories, Inc., Hercules, CA, USA) was used to measure protein concentrations (μg/mL) by using a Bio-Rad Model 680 microplate reader at a wavelength of 595 nm. For cytosolic and nuclear protein fractionation, we followed the protocol as described previously [ 60 ]. Next, acrylamide gel electrophoresis (with 10–15% acrylamide) was performed using aliquots of cell lysates containing 20 μg of total protein and then transferred to polyvinylidene fluoride membranes (Pall Corp, Prot Washington, NY, USA).…”

Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways

“…It is well-appreciated that these isoforms are involved in maintaining the stemness of CSCs across multiple cancer types, including breast, prostate, colorectal, pancreatic, melanoma, lung, liver, and brain [30][31][32][33][34][35][36]. Indeed, ALDH isoforms have been linked to enhanced clonogenicity and tumorigenicity, as well as chemoresistance and metastasis [13,30,31,33,37]. Recently, there has been increasing interest in the development of ALDH inhibitors to treat cancer and target aggressive CSC populations.…”

“…Similarly, daidzin, an isoflavone derived from the kudzu vine, has an IC50 of 80 nM and has been shown to reduce alcohol consumption in animal models [56,57]. In transwell migration assays, 25 µM of CVT-10216 reduced the migratory capacity of colorectal cancer cell lines HCT-116 and DLD-1 cell lines [13]. Similarly, 100 µM or 25 µM of daidzin reduced DLD-1 and HCT116 migration in transwell migration assays, respectively [13].…”

“…Similarly, 100 µM or 25 µM of daidzin reduced DLD-1 and HCT116 migration in transwell migration assays, respectively [13]. Furthermore, both inhibitors reduced the clonogenicity of the HCT-116 and DLD-1 cell lines; however, CVT-10216 exhibited increased efficacy as it reduced clonogenicity at 25 µM in HCT-116 cells, compared to 100 µM with daidzin [13].…”

“…The importance of CSCs in the development of chemoresistance has been demonstrated in cancers including breast, head and neck, mesothelioma, gastric, and ovarian cancers and have been extensively reviewed elsewhere [7][8][9][10][11]. Furthermore, CSCs have also been implicated as important contributors to metastasis across multiple cancer types [12][13][14][15][16][17][18]. Many current therapies that are designed to target fast proliferating bulk tumor cells are much less effective at clearing the highly aggressive and possibly quiescent CSC populations, which can ultimately lead to metastasis and recurrence [19][20][21].…”