Abstract
Aldehyde dehydrogenase 1A1 (ALDH1A1) is one of cancer stem cell (CSC) markers, and high ALDH1 expression has been related to drug resistance and facilitated tumor growth. In this study, we investigated the potential involvement of nuclear factor erythroid 2-like 2 (NFE2L2/NRF2) in CSC-like properties of ALDH-high ovarian CSCs. Our experimental system, ALDH1A1-high (ALDH-H) subpopulation, was isolated and stabilized using doxorubicin-resistant ovarian cancer A2780 cells. ALDH-H exerted CSC-like properties such as drug resistance, colony/sphere formation, and enhanced tumor growth along with high levels of CSCs markers compared to ALDH1A1-low (ALDH-L). Levels of NRF2 and subsequent target genes substantially increased in ALDH-H cells, and the increase in ALDH1A1 and p62 was associated with NRF2 upregulation. ALDH1A1-silencing blocked increases in NRF2, drug efflux transporters, and p62, along with CSC markers in ALDH-H cells. The inhibition of p62, which was elevated in ALDH-H, suppressed NRF2 activation. High NRF2 level was confirmed in the ALDH1-high subpopulation from colon cancer HCT116 cells. The functional implication of NRF2 activation in ovarian CSCs was verified by two experimental approaches. First, CSC-like properties such as high CSC markers, chemoresistance, colony/sphere formation, and tumor growth were significantly inhibited by NRF2-silencing in ALDH-H cells. Second, all-trans retinoic acid (ATRA) suppressed ALDH1 expression, inhibiting NRF2 activation, which led to the attenuation of CSC-like properties in ALDH-H cells but not in ALDH-L cells. These results provide insight into the molecular basis of the ALDH1A1-mediated development of CSC-like properties such as stress/treatment resistance, and further suggest the therapeutic potential of ATRA in ALDH-high ovarian CSCs.
Highlights
A small subpopulation of tumor cells, called cancer stem cells (CSCs) or tumor-initiating cells (TICs), are CSCs exhibit several characteristic properties, including enhanced self-renewal capacities, recurrence, and chemoresistance of tumor cells[6,7]
all-trans retinoic acid (ATRA) suppresses CSC-like properties only in aldehyde dehydrogenase (ALDH)-H cells Since ATRA treatment was found to downregulate the expression of CSC markers and NRF2 in ALDH-H cells, we explored the functional involvement of ATRA in CSClike properties of ALDH-H cells
High ALDH activity is attributed to the increased expression of ALDH1A1 in many types of cancer cells; ALDH1A1 isozyme is used as a marker for the enrichment of CSC subpopulations from tumors and cancer cell lines
Summary
A small subpopulation of tumor cells, called cancer stem cells (CSCs) or tumor-initiating cells (TICs), are CSCs exhibit several characteristic properties, including enhanced self-renewal capacities, recurrence, and chemoresistance of tumor cells[6,7]. Kim et al Cell Death and Disease (2018)9:896 protein (BCRP); and DNA repair enzymes contribute to therapy resistance and facilitated survival of CSCs8. The linkage between high ALDH expression and CSC-like properties of various cancers is supported by multiple lines of in vitro and clinical evidence. High ALDH expression showed a strong association with therapy resistance. ALDH1-positive CSC-like cells were enriched in ovarian tumors following the taxane/ platinum-based therapy[18]. In drug-resistant ovarian cancer cell lines, high expression of BCRP and multidrug resistance protein 1 (MDR1) was accompanied by ALDH1A1 overexpression, and the inhibition of ALDH activity reduced drug efflux transporter expression, leading to sensitization to chemotherapy[21]. There is insufficient evidence for the molecular role of ALDH1 in CSC-like properties, including the increased drug efflux transporters and enhanced tumorigenicity
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