Downregulation of MCF2L Promoted the Ferroptosis of Hepatocellular Carcinoma Cells through PI3K/mTOR Pathway in a RhoA/Rac1 Dependent Manner

Abstract

Backgound. Multiple patients with hepatocellular carcinoma (HCC) received sorafenib therapy presented primary or secondary chemoresistance. The underlying mechanisms of chemoresistance are rather vague, ferroptosis is a new kind of cell death, and its discovery provides new opportunities to overcome sorafenib resistance. Therefore, it is essential to investigate the regulators of ferroptosis and implement a corresponding therapy strategy. Methods and Results. The levels of MCF2L were detected by PCR and western blotting assay. The effect of MCF2L on ferroptosis was confirmed by MTT, colony formation assay, Brdu, in vivo animal experiment, and the content of Iron, GSH, ROS, and MDA. The underlying mechanisms were explored by PCR, western blotting, and affinity precipitation assay. Our findings demonstrated that MCF2L is remarkedly upregulated in HCC tissues, and sorafenib can induce the levels of MCF2L, suggesting that MCF2L might function in sorafenib resistance of HCC. Further analysis showed that downregulation of MCF2L enhances HCC cell death induced by sorafenib, and ferroptosis inhibitor can reverse this process. Subsequent experiments showed that downregulation of MCF2L elevates the content of Iron, ROS, and MDA, which are all indicators of ferroptosis. Finally, mechanism analysis showed that MCF2L regulates the PI3K/AKT pathway in a RhoA/Rac1 dependent manner. Conclusions. Our study showed that targeting MCF2L may be a hopeful method to overcome sorafenib-resistance through inducing ferroptosis in HCC.

Improved integration of single-cell transcriptome data demonstrates common and unique signatures of heart failure in mice and humans

“…6B ). In addition, many GTPase regulatory genes were found specifically increased in humans, including MCF2L and RASGRF2 , which are known to regulate RAC1 , and SPATA13 , which enables guanyl-nucleotide exchange factor activity [ 34 , 35 ]. In contrast, we observed that signaling pathways mainly dealing with energy metabolism were commonly regulated in patients with heart disease as well as in mouse models.…”

Iron accumulation and lipid peroxidation: implication of ferroptosis in hepatocellular carcinoma

“…( 110 ), curcumin promoted iron apoptosis in colorectal cancer by controlling the expression of vital iron apoptosis indicators Fer 1, SLC7A11, GSH, MDA, and ROS through the PI3K/mTOR pathway. Recent studies have shown that the mTOR-related signaling system can either promote or inhibit ferroptosis in hepatocellular carcinoma cells ( 111 , 112 ). For instance, HU et al.…”

“…Additionally, according to Chen et al (110), curcumin promoted iron apoptosis in colorectal cancer by controlling the expression of vital iron apoptosis indicators Fer 1, SLC7A11, GSH, MDA, and ROS through the PI3K/mTOR pathway. Recent studies have shown that the mTOR-related signaling system can either promote or inhibit ferroptosis in hepatocellular carcinoma cells (111,112). For instance, HU et al (113) found that miR-21-5p controlled the AKT/mTOR signaling pathway through MELK in vivo, reducing iron apoptosis in hepatocellular carcinoma cells.…”