Abstract
Ferroptosis, a type of cell death triggered by excessive accumulation of iron-dependent lipid peroxidation, possesses an excellent potential in cancer treatment. However, many colorectal cancer (CRC) cell lines are resistant to ferroptosis induced by erastin and RSL3, the classical ferroptotic inducers. Moreover, the underlying mechanism of resistance remains poorly elucidated. This study sought to discover the major factor contributing to ferroptosis resistance in CRC. The study findings will help design strategies for triggering ferroptosis for application in individualized tumor therapy. Here, we show that tetrahydrobiopterin (BH4) determines the sensitivity of CRC cells to ferroptosis induced by erastin. GTP cyclohydrolase-1 (GCH1) is the first rate-limiting enzyme of BH4. Genetic or pharmacological inhibition of GCH1 decreased BH4 and assisted erastin in cell death induction, lipid peroxidation enhancement, and ferrous iron accumulation. BH4 supplementation completely inhibited ferroptotic features resulting from GCH1 knockdown. Unexpectedly, GCH1 knockdown failed to enhance RSL3-induced cell death in CRC. Mechanistically, GCH1 knockdown drastically activated ferritinophagy during erastin treatment rather than RSL3 treatment. Administration of an autophagy inhibitor reversed erastin resistance in GCH1-knockdown cells. GCH1 inhibitor and erastin co-treatment in vivo synergistically inhibited tumor growth in CRC. Overall, our results identified GCH1/BH4 metabolism as a burgeoning ferroptosis defense mechanism in CRC. Inhibiting GCH1/BH4 metabolism promoted erastin-induced ferroptosis by activating ferritinophagy, suggesting that combining GCH1 inhibitors with erastin in the treatment of CRC is a novel therapeutic strategy.
Highlights
Colorectal cancer (CRC) is the second deadliest cancer worldwide (Bray et al, 2018)
The analysis of the association between GTP cyclohydrolase-1 (GCH1)/BH4 metabolism and colorectal cancer (CRC) cell ferroptosis was conducted in four human CRC cell lines, including HCT116, HT29, SW480, and Caco-2 cells
Our results demonstrated that GCH1/BH4 metabolism is a novel ferroptosis-resistant mechanism in CRC, entirely independent of the glutathione peroxidase 4 (GPX4) redox system
Summary
Colorectal cancer (CRC) is the second deadliest cancer worldwide (Bray et al, 2018). The global burden of CRC is expected to rise by 60% to more than 2.2 million new cases and 1.1 million deaths by 2030 (Arnold et al, 2017). Immunotherapy and molecular-targeted therapy are developing, chemotherapy is still a critical and conventional treatment for CRC (Benson et al, 2018; Parseghian et al, 2019; Xie et al, 2020). Chemotherapy is often limited by cancer cell. Silencing GCH1/BH4 Promote Ferroptosis in Colorectal Cancer resistance to chemotherapy drugs. Apoptosis suppression is a common drug-resistance mechanism that frequently occurs during or before treatment (Jeught et al, 2018; Wang, 2020). An urgent need exists to explore novel cell death mechanisms and their potential application in CRC treatment
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