Targeting Wnt/β‐catenin by anthelmintic drug niclosamide overcomes paclitaxel resistance in esophageal cancer

Abstract

Esophageal cancer is an aggressive malignancy, and its current treatment strategies are plagued with high rates of recurrence. In this work, we demonstrate that niclosamide, an anthelmintic drug, is a potential sensitizing candidate for overcoming chemoresistance in esophageal cancer. Using a panel of esophageal cancer cell lines and normal cells, we show that niclosamide has anti‐esophageal cancer activity and is likely to be less effective against normal esophageal epithelial and fibroblast cells. The combination of niclosamide with paclitaxel results in much greater efficacy than paclitaxel alone, suggesting that niclosamide is active against esophageal cancer cells that are resistant to paclitaxel. This is further confirmed by our results that niclosamide is effective in inhibiting proliferation and inducing apoptosis in paclitaxel‐resistant esophageal cancer cells. In line with the findings obtained from in vitro cell culture system, niclosamide augments the in vivo efficacy of paclitaxel and significantly arrests paclitaxel‐resistant esophageal cancer growth without causing toxicity in mice. Mechanistically, we show that niclosamide decreases β‐catenin level and activity, and inhibits phosphorylation of STAT3 and mTORC1 substrate 70S6K. Stabilization of β‐catenin level by Wnt activator lithium chloride (LiCl) significantly abolishes the inhibitory effects of niclosamide in inhibiting proliferation and survival but not suppressing phosphorylation of STAT3 and 70S6K in paclitaxel‐resistant esophageal cancer cells, suggesting that niclosamide sensitizes esophageal cancer cell to paclitaxel mainly through inhibiting Wnt/β‐catenin. Our work demonstrates the efficacy of niclosamide and its underlying mechanism in paclitaxel‐resistant esophageal cancer. Our work emphasizes that Wnt/β‐catenin inhibition is a sensitizing strategy in esophageal cancer.

Environmental Cadmium Exposure Promotes the Development, Progression and Chemoradioresistance of Esophageal Squamous Cell Carcinoma

“…the activation of Ras/Raf/MEK/ERK signaling cascade (Ju et al, 2017) and the activation of MAPK/ERK signaling pathway in human lung adenocarcinoma cells (Huff et al, 2016). It is clear that hyperactivated Wnt signaling plays critical role in the pathogenesis of esophageal cancer, cancer progression and chemo-and radio-resistance (Su et al, 2016;Wei et al, 2021). Our earlier observations in prolonged Cd-treated nasopharyngeal carcinoma cells showed that chronic Cd exposure aggravates malignant phenotypes of nasopharyngeal carcinoma by activating the Wnt/β-catenin signaling pathway via hypermethylation of the casein kinase 1α promoter (Peng et al, 2019).…”

Targeting the Wnt/β-catenin signaling pathway in cancer

“…Pyrvinium blocks Wnt signal by decreasing β-catenin levels and suppressing the transcription of β-catenin targeted genes. However, cancer cells with increasing level of β-catenin are no longer impacted by pyrvinium [72,73]. In addition, a novel small-molecule CK1α activator called SSTC3 has been proved to inhibit the growth of CRC xenografts in mice and also attenuate the growth of patient-derived metastatic CRC xenograft [74,75].…”

Ginsenoside Rh4 Suppresses Metastasis of Esophageal Cancer and Expression of c-Myc via Targeting the Wnt/β-Catenin Signaling Pathway

“…Wnt is a crucial part of cell axis patterning, including movement. β-catenin (β series protein) is an adhesion factor, and recent studies have found that it has the dual function of regulating and coordinating cell adhesion and gene transcription [ 46 , 47 ]. HLY78 is an agonist of the Wnt/β-catenin signaling pathway.…”