IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer

Abstract

Ferroptosis, implicated in several diseases, is a new form of programmed and nonapoptotic cell death triggered by iron-dependent lipid peroxidation after inactivation of the cystine/glutamate antiporter system xc–, which is composed of solute carrier family 7 membrane 11 (SLC7A11) and solute carrier family 3 membrane 2 (SLC3A2). Therefore, inducing ferroptosis through inhibiting the cystine/glutamate antiporter system xc– may be an effective way to treat cancer. In previous screening tests, we found that the benzopyran derivative 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) significantly inhibited the viability of colorectal cancer cells. However, the impact of IMCA on ferroptosis remains unknown. Hence, this study investigated the effect of IMCA on ferroptosis and elucidated the underlying molecular mechanism. Results showed that IMCA significantly inhibited the cell viability of colorectal cancer cells in vitro and inhibited tumor growth with negligible organ toxicity in vivo. Further studies showed that IMCA significantly induced the ferroptosis of colorectal cancer cells. Mechanistically, IMCA downregulated the expression of SLC7A11 and decreased the contents of cysteine and glutathione, which resulted in reactive oxygen species accumulation and ferroptosis. Furthermore, overexpression of SLC7A11 significantly attenuated the ferroptosis caused by IMCA. In addition, IMCA regulated the activity of the AMPK/mTOR/p70S6k signaling pathway, which is related to the activity of SLC7A11 and ferroptosis. Collectively, our research provided experimental evidences on the activity and mechanism of ferroptosis induced by IMCA and revealed that IMCA might be a promising therapeutic drug for colorectal cancer.

Dihydrotanshinone I inhibits human glioma cell proliferation via the activation of ferroptosis

“…These processes are caused by the loss of intracellular GPX4 activity. The cell membrane-localized system Xc-is composed of SLC3A2 and SLC7A11 (58). SLC3A2 is a binding protein of SLC7A11, which takes up cystine and excretes glutamate (58).…”

“…The cell membrane-localized system Xc-is composed of SLC3A2 and SLC7A11 (58). SLC3A2 is a binding protein of SLC7A11, which takes up cystine and excretes glutamate (58). In cell metabolism, GSH is synthesized from cystine and is an important antioxidant in the cell (59).…”

Amino Acid Transporters on the Guard of Cell Genome and Epigenome

“…LATs are the light subunits of the heterodimeric transmembrane amino acid transporter complexes (HATC) forming the heterodimers with the heavy subunits of SLC3 family: SLC3A1 and SLC3A2 [ 47 ]. In general, members of SLC3 and SLC7 families are essential for mTOR pathway activation as reviewed in [ 26 ], and for the regulation of autophagy and ferroptosis by balancing intracellular AA and ROS levels [ 48 , 49 , 50 , 51 , 52 , 53 , 54 ].…”

“…These mechanisms repress protein synthesis and trigger the expression of ATF4, which regulates the transcription of multiple targets involved in amino acid metabolism and stress response [ 61 , 62 ]. In particular, ATF4 is essential for the expression of SLC7A5, SLC7A11, and SLC3A2 and, therefore, for the replenishment of the intracellular GSH precursors [ 51 , 62 , 63 , 64 , 65 ]. The ATF4 knockout (KO) cells possess an impaired amino acid import and GSH biosynthesis and are highly predisposed to oxidative stress [ 62 ].…”

Insight Into the Role of Ferroptosis in Non-neoplastic Neurological Diseases

“…Additionally, glutamate excitotoxicity is involved in the pathogenesis of AD. Dysfunction of systeme x c − during ferroptosis can lead to an increase in the concentration of extracellular glutamate, causing excitotoxicity (Kang et al, 2018 ; Zille et al, 2019 ; Zhang et al, 2020 ). Furthermore, oxidative stress is critically related to AD.…”