The central role of a two‐way positive feedback pathway in molecular targeted therapies‐mediated pyroptosis in anaplastic thyroid cancer

Abstract

Background Anaplastic thyroid carcinoma (ATC) is one of the most aggressive tumours. We previously confirmed that apatinib has potential therapeutic effects on ATC via regulated cell death (RCD). As a newly identified RCD, pyroptosis demonstrates direct antitumour activity different from apoptosis or autophagy. Therefore, the clinical significance, regulatory role and underlying mechanisms of pyroptosis in ATC were focused on in this study. Methods In a phase II trial, patients with anaplastic or poorly differentiated thyroid carcinoma received apatinib 500 mg once daily. Multiple assays were implemented to evaluate the antitumour efficacy of apatinib and/or melittin in vitro and in vivo. High‐throughput sequencing was applied to analyse differential mRNAs expression in ATC cells treated by apatinib with or without melittin. In situ Hoechst 33342/PI double‐staining, LDH release assay and enzyme‐linked immunosorbent assay (ELISA) were employed to determine pyroptosis. In mechanism exploration, quantitative RT‐PCR, Western blotting and si‐RNA knocking down were executed. Results Seventeen patients were evaluable. Apatinib showed a promising therapeutic effect by a disease control rate (DCR) of 88.2%; however, treatment was terminated in 23.5% of patients due to intolerable toxicity. To reduce adverse events, a pyroptosis‐mediated synergistic antitumour effect of apatinib and melittin was identified in treatment of ATC in vitro and in vivo. The caspase‐1–gasdermin D (GSDMD) axis‐mediated pyroptosis was the key to extra antitumour effect of the combination of apatinib and melittin. Moreover, caspase‐3–gasdermin E (GSDME) pyroptosis pathway also functioned importantly in addition to caspase‐1–GSDMD pathway. Evidenced by in vitro and in vivo study, a two‐way positive feedback interaction was innovatively confirmed between caspase‐1–GSDMD and caspase‐3–GSDME axes. Conclusions Through pyroptosis mediated by caspase‐1–GSDMD and caspase‐3–GSDME axes synchronically, low‐dosage apatinib and melittin could synergistically achieve a comparable therapeutic potential with reduced AEs. More importantly, a two‐way positive feedback interaction is innovatively proposed between these two axes, which provide a new prospect of targeted therapy.

Apatinib: A Novel Antiangiogenic Drug in Monotherapy or Combination Immunotherapy for Digestive System Malignancies

“…Antiproliferative as a kind of important feature in apatinib has been addressed by researchers. For example, Zhijian (80). Our previous study indicated that after apatinib treatment ER stress could induce autophagy in colorectal cancer cell lines through the IRE1a pathway.…”

“…Mechanistically, upregulated cleaved caspase-1 activated caspase-3 by generating GSDMD-N terminal, while cleaved caspase-3 enhanced caspase-1 activation which could induce pyroptosis by GSDME-N and vice versa. These processes constitute a unique system involving two-way positive feedback regulation ( 80 ). Our previous study indicated that after apatinib treatment ER stress could induce autophagy in colorectal cancer cell lines through the IRE1α pathway.…”

Elucidating the role of Pyroptosis in papillary thyroid cancer: prognostic, immunological, and therapeutic perspectives

“…The model showed a significant increase in tumor immune cell infiltration in the low-risk group. Zhao et al identified a novel antitumor effect of pyroptosis induced by the combination of apatinib and melittin in anaplastic THCA [ 33 ]. The distinct effects of pyroptosis in different thyroid diseases reflect complex molecular regulatory mechanisms.…”

Non-Apoptotic Programmed Cell Death in Thyroid Diseases

“…Melittin, an isolated water-soluble peptide derived from honeybee venom, is used to alleviate chronic inflammation [155]. Apatinib, in the presence of melittin, induces recruitment and activation of inflammatory vesicles and leads to pyroptosis and enhanced antitumor effects of apatinib [156]. This suggests that apatinib in mesenchymal or invasive TC shows promising therapeutic benefits.…”

“…Furthermore, low-dose apatinib synergistically achieves comparable therapeutic potential with melittin, thereby reducing adverse events. The positive feedback modulation may improve the therapeutic efficacy of antiangiogenic targeted agents, offering new prospects for targeted therapy [156].…”