Deferasirox Targets TAOK1 to Induce p53-Mediated Apoptosis in Esophageal Squamous Cell Carcinoma

TL;DR

This study shows that Deferasirox, an iron chelator, can target TAOK1 to trigger p53-mediated cell death in esophageal cancer cells, both in lab and animal models.

Contribution

The study identifies TAOK1 as a novel target for Deferasirox in ESCC and reveals a p53-mediated apoptotic mechanism.

Findings

Deferasirox inhibits ESCC cell proliferation and colony formation in a dose- and time-dependent manner.

TAOK1 inhibition by Deferasirox activates p53-mediated apoptosis, as shown by increased expression of apoptotic markers.

In vivo experiments show Deferasirox reduces tumor volume in PDX models without toxicity.

Abstract

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with a poor prognosis and limited effective treatment options. This study investigates the therapeutic potential of Deferasirox (DFO), an iron chelator, in ESCC by targeting TAOK1, an STE20-type kinase implicated in cancer development. We demonstrate that DFO significantly inhibits the proliferation and colony formation of ESCC cells in a dose- and time-dependent manner. Mechanistic investigations reveal that DFO binds directly to TAOK1 and reduces its kinase activity. Proteomics and phosphorylated proteomic sequencing analysis further reveal that TAOK1 knocking down dramatically increased p53-mediated apoptosis. Moreover, the inhibition of TAOK1 by DFO or lenti-virus infection induces apoptosis in ESCC cells, as evidenced by the increased expression of p53, p-p53 (S15), p-p53 (S46), Puma, Noxa, and Bax, and the decreased expression of Bcl-2. Furthermore, in vivo studies using patient-derived xenograft (PDX) mouse models show that DFO treatment significantly reduces tumor volume without observable toxicity. Histological and immunohistochemical analyses confirm the down-regulation of TAOK1 and Ki-67, and the up-regulation of p53 expression in DFO-treated tumors. Our findings suggest that DFO exerts its antitumor effects in ESCC by targeting TAOK1, providing a potential therapeutic strategy for ESCC patients.

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