Cell Signal Transduction Laboratory, Bioinformatics Center, Laboratory for Nanomedicine, Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China.
Department of Dermatology, Second People's Hospital of Zhengzhou, Zhengzhou 450006, China.
Oxid Med Cell Longev. 2020 Apr 3;2020:1675613. doi: 10.1155/2020/1675613. eCollection 2020.
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 and inhibited tumor growth with negligible organ toxicity . 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.
铁死亡是一种新的程序性非细胞凋亡死亡方式，在胱氨酸/谷氨酸逆向转运蛋白系统 xc 失活后，由铁依赖性脂质过氧化引发，该系统由溶质载体家族 7 膜 11（SLC7A11）和溶质载体家族 3 膜 2（SLC3A2）组成。因此，通过抑制胱氨酸/谷氨酸逆向转运蛋白系统 xc 诱导铁死亡可能是治疗癌症的一种有效方法。在之前的筛选测试中，我们发现苯并吡喃衍生物 2-亚氨基-6-甲氧基-2H-色烯-3-甲酰胺（IMCA）显著抑制结直肠癌细胞的活力。然而，IMCA 对铁死亡的影响尚不清楚。因此，本研究探讨了 IMCA 对铁死亡的影响，并阐明了其潜在的分子机制。结果表明，IMCA 显著抑制结直肠癌细胞的活力，并抑制肿瘤生长，而对器官几乎没有毒性。进一步的研究表明，IMCA 显著诱导结直肠癌细胞的铁死亡。机制上，IMCA 下调 SLC7A11 的表达，降低半胱氨酸和谷胱甘肽的含量，导致活性氧物质的积累和铁死亡。此外，SLC7A11 的过表达显著减弱了 IMCA 引起的铁死亡。此外，IMCA 调节 AMPK/mTOR/p70S6k 信号通路的活性，该通路与 SLC7A11 和铁死亡的活性有关。总之，本研究为 IMCA 诱导的铁死亡的活性和机制提供了实验证据，并表明 IMCA 可能是治疗结直肠癌的一种有前途的治疗药物。
