All-trans retinoic acid downregulates ALDH1-mediated stemness and inhibits tumour formation in ovarian cancer cells

Abstract

Aldehyde dehydrogenase 1 (ALDH1) is a cancer stem-like cell (CSC) marker in human cancers; however, the specific ALDH1-regulated function and its underlying signalling pathways have not been fully demonstrated. Here, we investigated the ALDH1-regulated function and its underlying signalling and tested whether all-trans retinoic acid (ATRA) can suppress ALDH1-regulated tumour behaviour in ovarian cancer cells. By modulating ALDH1 expression using flow cytometry enrichment and exogenous overexpression or knockdown, we showed that the ALDH1 activity is positively correlated with stemness in ovarian cancer cells according to measures such as sphere formation and CSC marker expression as well as tumourigenesis in a mouse xenograft model. The findings indicate that the ALDH1 directly regulates the functions of ovarian cancer cells. We also showed that ALDH1 can regulate the expression of FoxM1 and Notch 1, which are involved in the downstream signalling of ALDH1-mediated biofunctions. Inhibition of FoxM1 by Thiostrepton and of Notch1 by DAPT downregulated the sphere formation ability of cells. ATRA reduced ALDH1 expression, suppressed tumour formation and inhibited sphere formation, cell migration and invasion in ALDH1-abundant ovarian cancer cells. We conclude that ATRA downregulates ALDH1/FoxM1/Notch1 signalling and suppresses tumour formation in ovarian cancer cells.

High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling

“…Lung cancer cells with high ALDH1 activity treated with ATRA decreased ALDH1A1 protein levels without affecting mRNA levels, resulting in sensitization to 4-hydroperoxycyclophosphamide 25 . ATRA reduced ALDH1A1 levels and inhibited sphere formation and invasion in ALDH1-high cisplatin-resistant ovarian cancer cells 62 . Similarly, the inhibitory effect of ATRA on ALDH1 was confirmed in our system: ATRA effectively reduced ALDH1A1 expression and inhibited CSC marker expression, tumor growth, and colony/sphere formation.…”

The NOTCH1-HEY1 pathway regulates self-renewal and epithelial-mesenchymal transition of salivary adenoid cystic carcinoma cells

“…In addition, we also examined the expression of OCT4 and ALDH1, known CSC markers, which was also downregulated. Aldehyde dehydrogenase 1 (ALDH1) is a cancer stem cell-like cell (CSC) marker in human cancer that is involved in the regulation of NOTCH1 signaling and regulates the formation of ovarian cancer tumor spheres [38,47]. In HNSCC, OCT4 is considered a key regulator of CSCs, which targets CSCs and may be of potential value in the treatment of HNSCC [48].…”

Prognostic roles of Notch receptor mRNA expression in human ovarian cancer

“…Notch1 was widely reported in ovarian carcinogenesis and was the best studied among Notch ligands and four Notch receptors [12–15]. The active form of Notch 1, the Notch 1 intracellular domain (NICD), was detected in ovarian cancer cell lines, ovarian cancer specimens and may led to growth inhibition of ovarian cancer cells upon depletion of Notch 1 by Notch 1 siRNA [42].…”