Interaction mechanisms between autophagy and ferroptosis: Potential role in colorectal cancer

Abstract

Colorectal cancer (CRC) is a common malignancy that has the second highest incidence and mortality rate. Although there are many personalized treatment options for CRC, the therapeutic effects are ultimately limited by drug resistance. Studies have aimed to block the initiation and progression of CRC by inducing cell death to overcome this obstacle. Substantial evidence has indicated that both autophagy and ferroptosis play important regulatory roles in CRC. Autophagy, a lysosome-dependent process by which cellular proteins and organelles are degraded, is the basic mechanism for maintaining cell homeostasis. The duality and complexity of autophagy in cancer therapy is a hot topic of discussion. Ferroptosis, a regulated cell death pathway, is associated with iron accumulation-induced lipid peroxidation. The activation of ferroptosis can suppress CRC proliferation, invasion and drug resistance. Furthermore, recent studies have suggested an interaction between autophagy and ferroptosis. Autophagy can selectively degrade certain cellular contents to provide raw materials for ferroptosis, ultimately achieving antitumor and anti-drug resistance. Therefore, exploring the interaction between autophagy and ferroptosis could reveal novel ideas for the treatment of CRC. In this review, we describe the mechanisms of autophagy and ferroptosis, focusing on their roles in CRC and the crosstalk between them.

Keywords: Autophagy; Cell death; Colorectal cancer; Ferroptosis; Iron; Lipid peroxidation.

Figure 1

Mechanisms of ferroptosis (created by Figdraw). TXNRD1: Thioredoxin reductase 1; GSS: Glutathione synthetase; GSH: Glutathione; GSSG: Oxidized glutathione; GSR: Glutathione-disulfide reductase; GPX4: Glutathione peroxidase 4; PLOOH: Phospholipid hydroperoxides; PLOH: Phosphatidyl alcohol; Fe³⁺: Ferric ion; Fe²⁺: Ferrous ion; TF: Transferrin; TfR1: Transferrin receptor 1; STEAP3: Six-transmembrane epithelial antigen of prostate 3; LIP: labile iron pool; H₂O₂: Hydrogen peroxide; HO•: Hydroxyl radicals; PL•: Phospholipid radical; PLH: Phospholipid; PLO•: Phospholipid alkoxyl radical; PLOO•: Phospholipid peroxyl radical; PUFAs: Polyunsaturated fatty acids; PUFA-PL: Polyunsaturated-fatty-acid-containing phospholipid; ACSL4: Acyl-CoA synthetase long-chain family member 4; LPCAT3: Lysophosphatidylcholine acyltransferase 3; LOXs: Lipoxygenases; NRF2: Nuclear factor erythroid 2-related factor 2; HO-1: Haem oxygenase 1; FSP1: Ferroptosis suppressor protein 1; CoQ₁₀: Ubiquinone; CoQ₁₀H₂: The reduced form of ubiquinone; p53: Tumor protein p53; DPP4: Dipeptidyl-peptidase-4; NOX1: A member of the NADPH oxidase protein family.

Figure 2

The interaction mechanisms between autophagy and ferroptosis in colorectal cancer (created by Figdraw). Fe²⁺: Ferrous ions; FTH1: Ferritin heavy chain 1; FTL: Ferritin light chain; NCOA4: Nuclear receptor coactivator 4; AMPK: Adenosine monophosphate-activated protein kinase; BECN1: Beclin1; p62: sequestosome 1; NRF2: Nuclear factor erythroid 2-related factor 2; KEAP1: Kelch-like ECH-associated protein 1; GPX4: Glutathione Peroxidase 4; LDs: Lipid droplets; Rab7: The small GTPase; HSC70: Heat shock cognate 71 kDa protein; HSP90: Heat shock protein 90; LAMP2A: Lysosome-associated membrane protein type 2A; CMA: Chaperone-mediated autophagy.