Atranorin driven by nano materials SPION lead to ferroptosis of gastric cancer stem cells by weakening the mRNA 5-hydroxymethylcytidine modification of the Xc-/GPX4 axis and its expression

Abstract

Gastric cancer is a highly malignant tumor. Gastric cancer stem cells (GCSCs) are the main causes of drug resistance, metastasis, recurrence, and poor prognosis. As a secondary metabolite of lichen, Atranorin has a variety of biological effects, such as antibacterial, anti-inflammatory, analgesic, and wound healing; however, its killing effect on GCSCs has not been reported. In this study, we constructed Atranorin complexes comprising superparamagnetic iron oxide nanoparticles (SPION) (Atranorin@SPION). In vitro and in vivo experiments confirmed that Atranorin@SPION could significantly inhibit the proliferation, invasion, angiogenesis, and tumorigenicity of CD44+/ CD24+ GCSCs, and induce oxidative stress injury, Fe 2 + accumulation, and ferroptosis. Quantitative real-time reverse transcription PCR and western blotting results showed that Atranorin@SPION not only reduced the expression levels of GCSC stem cell markers and cell proliferation and division markers, but also significantly inhibited the expression levels of key molecules in the cystine/glutamate transporter (Xc-)/glutathione peroxidase 4 (GPX4) and Tet methylcytosine dioxygenase (TET) family proteins. The results of high performance liquid chromatography-mass spectrometry and Dot blotting showed that Atranorin@SPION significantly inhibited the mRNA 5‑hydroxymethylcytidine modification of GCSCs. Meanwhile, the results of RNA immunoprecipitation-PCR also indicated that Atranorin@SPIONs significantly reduced the 5-hydroxymethylcytidine modification level of GPX4 and SLC7A11 mRNA 3' untranslated region in GCSCs, resulting in a decrease in their stability, shortening their half-lives and reducing translation activity. Therefore, this study revealed that Atranorin@SPIONs induced ferroptosis of GCSCs by weakening the expression of the Xc-/GPX4 axis and the 5-hydroxymethylcytidine modification of mRNAs in the pathway, thereby achieving their therapeutic effect on gastric cancer.

Lichen Depsides and Tridepsides: Progress in Pharmacological Approaches

“…The killing effect of atranorin on gastric cancer was also studied using complexes formed by superparamagnetic iron oxide nanoparticles (SPION) and atranorin. In vitro results on gastric cancer stem cells showed a reduction in proliferation, invasion, and tumorigenicity by reducing the expression of members of the Xc-/GPX4 axis and their mRNA 5-hydroxymethylcytidine modification and by inducing ferroptosis [ 54 ].…”

“…Comparing the effects of atranorin on normal mammary epithelial NMuMG cells and 4T1 cancer cells, it was observed that 4T1 cells were more sensitive to atranorin, reducing the clonogenic ability of carcinoma (75 µM), inducing apoptosis mediated by caspase-3 activation and poly ADP ribose polymerase (PARP) cleavage, and enhancing the depletion of Bcl-xL protein [ 57 ]. Moreover, atranorin SPION complexes showed tumorgenicity reduction in NOD-scid mice [ 54 ].…”

Cancer stem cells: Signaling pathways and therapeutic targeting

“…This occurs through a combined therapeutic effect involving DOX chemotherapy and magnetic MSNs MFH under the influence of an alternating magnetic field. 371 Moreover, antibodymodified NPs, particularly those targeting lung CSCs, have shown enhanced cellular uptake and prolonged tumor accumulation, effectively eliminating up to 98% of lung CSCs in in vivo models. The combination of hyperthermia and chemotherapy exhibited significant inhibition of tumor growth and metastasis in mice carrying lung CSC xenografts, with minimal side effects and adverse reactions.…”

“…Biomimetic magnetic NPs have exhibited the ability to induce apoptosis in stress‐escape CSCs and impede their proliferation and metastasis both in vitro and in vivo. This occurs through a combined therapeutic effect involving DOX chemotherapy and magnetic MSNs MFH under the influence of an alternating magnetic field 371 . Moreover, antibody‐modified NPs, particularly those targeting lung CSCs, have shown enhanced cellular uptake and prolonged tumor accumulation, effectively eliminating up to 98% of lung CSCs in in vivo models.…”

Ferroptosis: Potential opportunities for natural products in cancer therapy

“…Several studies have improved the physicochemical properties and bioavailability of natural products by developing novel drug delivery systems and carriers (Z. Ni, Nie, et al, 2022;Z. Zhang, Ji, et al, 2022).…”