Abstract
Niclosamide is a traditional anti-tapeworm drug that exhibits potent anti-cancer activity. Our previous study showed that niclosamide induces cell cycle arrest in G1 phase. Nevertheless, the underlying mechanism remains unknown. The following study investigated the molecular mechanism through which niclosamide induced G1 arrest in head and neck squamous cell carcinoma (HNSCC) cell lines. The effect of niclosamide on human HNSCC cell line WSU-HN6 and CNE-2Z were analyzed using IncuCyte ZOOMTM assay, flow cytometry (FCM), real-time PCR and western blot. Luciferase assay was conducted to demonstrate the interaction between let-7d (a let-7 family member which functions as a tumor suppressor by regulating cell cycle) and 3′UTR of CDC34 mRNA. Xenografts tumor model was established to evaluate the niclosamide treatment efficacy in vivo. Briefly, an exposure to niclosamide treatment led to an increased let-7d expression and a decreased expression of cell cycle regulator CDC34, finally leading to G1 phase arrest. Moreover, an overexpression of let-7d induced G1 phase arrest and downregulated CDC34, while the knockdown of let-7d partially rescued the niclosamide-induced G1 phase arrest. Luciferase assay confirmed the direct inhibition of CDC34 through the targeting of let-7d. Furthermore, niclosamide markedly inhibited the xenografts growth through up-regulation of let-7d and down-regulation of CDC34. To sum up, our findings suggest that niclosamide induces cell cycle arrest in G1 phase in HNSCC through let-7d/CDC34 axis, which enriches the anti-cancer mechanism of niclosamide.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is a common disease found in the head and neck region (Siegel et al, 2017)
Our results indicated that non-coding RNA let-7d/CDC34 axis contributes to niclosamide-induced G1 cell cycle arrest in HNSCC
While diverse therapies for HNSCC have been developed over the years, chemotherapy has been used as palliation therapy for advanced disease; while concomitant chemotherapy has been applied as an auxiliary surgery or radiotherapy
Summary
Head and neck squamous cell carcinoma (HNSCC) is a common disease found in the head and neck region (Siegel et al, 2017). The 5 years survival for HNSCC is lower than 60%, which is inconsistent with the great advances in treatment approach, including surgery, digital guided technology, radio-, chemo-, and targeted immunotherapy (Chang and Wang, 2016). Recent studies have shown that niclosamide exhibits a potent anti-cancer activity (Pan et al, 2012; Chen et al, 2018). The precise mechanism of its antitumor is still not well demonstrated, niclosamide is defined as an oxidative phosphorylation uncoupler (Satoh et al, 2016). All these evidences indicate that niclosamide is a promising anticancer reagent. Isniclosamide have been used in Phase I and Phase II clinical trials for cancer management
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