Erianin Induces Ferroptosis of Renal Cancer Stem Cells via Promoting ALOX12/P53 mRNA N6-methyladenosine Modification

Abstract

Renal cell carcinoma (RCC) is the most common type of primary renal parenchymal malignancy in adults, with a high degree of malignancy and poor prognosis. Human renal cancer stem cells (HuRCSCs) are reported to be the main cause of drug resistance, metastasis, recurrence, and poor prognosis. Erianin is a low molecular-weight bibenzyl natural product extracted from Dendrobium chrysotoxum, which inhibits the in vitro and in vivo activity of a variety of cancer cells. However, the molecular mechanisms of Erianin's therapeutic effect on HuRCSCs are unknown. Here, we isolated CD44+/CD105+ HuRCSCs from patients with renal cell carcinoma. The experiments confirmed that Erianin significantly inhibited the proliferation, invasion, angiogenesis, and tumorigenesis of HuRCSCs, and induced oxidative stress injury and Fe 2+ accumulation. qRT-PCR and western blotting showed that Erianin significantly reduced the expression levels of cellular Ferroptosis protective factors, and upregulated the expression of METTL3 and downregulated that of FTO. Dot blotting results indicated that Erianin significantly upregulated the mRNA N6-methyladenosine (m6A) modification of HuRCSCs. The results of RNA immunoprecipitation-PCR also indicated that Erianin significantly enhanced the m6A modification level of the 3' untranslated region of ALOX12 and P53 mRNA in HuRCSCs, resulting in increased stability, prolonged half-life, and improved translation activity. In addition, clinical data analysis showed that the expression of FTO correlated negatively with adverse events in patient with renal cell carcinoma. Thus, this study suggested that Erianin can induce Ferroptosis in renal cancer stem cells by promoting N6-methyladenosine modification of ALOX12/P53 mRNA, ultimately achieving a therapeutic effect on renal cancer.

Erianin inhibits tumor growth by promoting ferroptosis and inhibiting invasion in hepatocellular carcinoma through the JAK2/STAT3/SLC7A11 pathway

“…Erianin might be a new inducer of ferroptosis, which induced ferroptosis in lung cancer cells by enhancing intracellular Ca 2+ concentration and CaM protein level 24 . Erianin enhanced ALOX12 m6A methylation and P53 by promoting m6A methyltransferase METTL3 expression, leading to ferroptosis of RCC stem cells 25 . Here, we found that erianin exerted a very considerable inhibitory effect on the proliferation and invasion ability of HCC cells.…”

“…24 Erianin enhanced ALOX12 m6A methylation and P53 by promoting m6A methyltransferase METTL3 expression, leading to ferroptosis of RCC stem cells. 25 Here, we found that erianin exerted a very considerable inhibitory effect on the proliferation and invasion ability of HCC cells. Besides, erianin pretreatment significantly increased ROS, total iron, Fe 2+ , and MDA content, thereby inducing apoptosis in HCC cells through ferroptosis.…”

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

“…124 Modifications in mRNA can affect its stability, readability, and translation efficiency, 125 and m6A modification in TP53 mRNA can upregulate p53 expression. 126 Nm modification on rRNA 127 and ψ modification on snRNA 128 can indirectly affect p53 expression. Epigenetic regulation complexly and precisely regulates the transcription and translation of the TP53 gene, affecting p53 levels and participating in various disease processes, particularly cancer regulation.…”

“…DNA methyltransferase inhibitors such as 5‐aza‐2'‐deoxycytidine can downregulate methylation levels in the TP53 promoter region, facilitating the binding of transcription factors and promoting TP53 expression 124 . Modifications in mRNA can affect its stability, readability, and translation efficiency, 125 and m6A modification in TP53 mRNA can upregulate p53 expression 126 . Nm modification on rRNA 127 and ψ modification on snRNA 128 can indirectly affect p53 expression.…”

Ferroptosis: Potential opportunities for natural products in cancer therapy

“…Further studies have shown that sulforaphane activates PI3K and increases the expression of IRP2 and DMT1 in MGC‐803 cells, while PI3K inhibition eliminates the increase in IRP2 and DMT1 expression, indicating that sulforaphane inhibits the development of gastric carcinoma by regulating the PI3K/IRP2/DMT1 axis (Wen et al, 2023). Furthermore, erianin extracted from Dendrobium chrysotoxum increased the N6‐methyladenosine modification of P53 and arachidonate 12‐lipoxygenase (ALOX12) mRNA by promoting methyltransferase‐like 3 (METTL3) expression, which enhanced ferroptosis in renal cancer stem cells by increasing the expression of these proteins (H. Shen et al, 2023). Overall, bioactive natural products are potential regulators of ferroptosis, which induce cancer cell death by targeting a variety of ferroptosis‐related proteins or pathways (Figure 5).…”