Dehydroepiandrosterone (DHEA) Sensitizes Irinotecan to Suppress Head and Neck Cancer Stem-Like Cells by Downregulation of WNT Signaling

Abstract

PurposeCurrent treatment options for head and neck squamous cell carcinoma (HNSCC) are limited, especially for cases with cancer stem cell-induced chemoresistance and recurrence. The WNT signaling pathway contributes to maintenance of stemness via translocation of β-catenin into the nucleus, and represents a promising druggable target in HNSCC. Dehydroepiandrosterone (DHEA), a steroid hormone, has potential as an anticancer drug. However, the potential anticancer mechanisms of DHEA including inhibition of stemness, and its therapeutic applications in HNSCC remain unclear.MethodsFirstly, SRB assay and sphere formation assay were used to examine cellular viability and cancer stem cell-like phenotype, respectively. The expressions of stemness related factors were measured by RT-qPCR and western blotting. The luciferase reporter assay was applied to evaluate transcriptional potential of stemness related pathways. The alternations of WNT signaling pathway were measured by nuclear translocation of β-catenin, RT-qPCR and western blotting. Furthermore, to investigate the effect of drugs in vivo, both HNSCC orthotopic and subcutaneous xenograft mouse models were applied.ResultsWe found that DHEA reduced HNSCC cell viability, suppressed sphere formation, and inhibited the expression of cancer-stemness markers, such as BMI-1 and Nestin. Moreover, DHEA repressed the transcriptional activity of stemness-related pathways. In the WNT pathway, DHEA reduced the nuclear translocation of the active form of β-catenin and reduced the protein expression of the downstream targets, CCND1 and CD44. Furthermore, when combined with the chemotherapeutic drug, irinotecan (IRN), DHEA enhanced the sensitivity of HNSCC cells to IRN as revealed by reduced cell viability, sphere formation, expression of stemness markers, and activation of the WNT pathway. Additionally, this combination reduced in vivo tumor growth in both orthotopic and subcutaneous xenograft mouse models.ConclusionThese findings indicate that DHEA has anti-stemness potential in HNSCC and serves as a promising anticancer agent. The combination of DHEA and IRN may provide a potential therapeutic strategy for patients with advanced HNSCC.

Protein Expression and Bioinformatics Study of Granulosa Cells of Polycystic Ovary Syndrome Expressed Under the Influence of DHEA

“…In this study, exposure of CGCs obtained from PCOS patients to DHEAS reduced the expression of a number of proteins, which could be due to downregulation of the WNT signaling pathway, as mentioned in recently published literature, irrespective of the source of cells and pathological conditions. 48 Adiponectin protein expression in MGCs was found to be involved in periovulatory remodeling of vascular endothelial growth factor genes and ovarian follicles. 49 The MAPK signaling pathway, which is 1 of the 2 best-characterized insulin signaling pathways, was also observed in our investigation.…”

“…In this study, exposure of CGCs obtained from PCOS patients to DHEAS reduced the expression of a number of proteins, which could be due to downregulation of the WNT signaling pathway, as mentioned in recently published literature, irrespective of the source of cells and pathological conditions. 48…”

Combinations of PRI-724 Wnt/β-Catenin Pathway Inhibitor with Vismodegib, Erlotinib, or HS-173 Synergistically Inhibit Head and Neck Squamous Cancer Cells

“…The presence of CSCs was also detected in HNSCCs, and targeting this subpopulation of cells has become a potential new therapeutic strategy [ 9 , 10 , 14 , 17 , 18 ]. Importantly, Wnt/β-catenin pathway inhibition had anti-stemness potential in HNSCC cells [ 19 ]. Indeed, this pathway maintains the activity of both normal and cancer stem cells [ 10 ].…”