Chrysin induces autophagy-dependent ferroptosis to increase chemosensitivity to gemcitabine by targeting CBR1 in pancreatic cancer cells
Chrysin induces autophagy-dependent ferroptosis to increase chemosensitivity to gemcitabine by targeting CBR1 in pancreatic cancer cells
复制标题
白杨素通过靶向胰腺癌细胞中的 CBR1 诱导自噬依赖性铁死亡以增加对吉西他滨的化疗敏感性
DOI：
10.1016/j.bcp.2021.114813
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发表时间：
2021-10-23
影响因子：
5.8
通讯作者：
Xu, Maolei
中科院分区：
文献类型：
--
作者：
Zhou, Ling;Yang, Chen;Xu, Maolei
最近的研究证实，诱导活性氧（ROS）是吉西他滨抗肿瘤的作用机制之一。人羰基还原酶1（CBR1）在保护细胞免受氧化损伤中起重要作用。然而，目前尚不清楚CBR1是否参与胰腺癌（PC）进展和吉西他滨耐药。基于GEPIA数据库，我们使用免疫组化（IHC）分析了PC患者的肿瘤组织样本，发现CBR1在PC组织中高度表达，并且这与PC的临床病理特征显著相关。CBR1基因抑制通过调节ROS的产生抑制PC细胞增殖。此外，吉西他滨上调CBR1表达，这可能限制吉西他滨的抗肿瘤活性，并且CBR1的衰减增强了体外和体内吉西他滨的敏感性。此外，我们报告白杨素直接结合到CBR1，抑制其酶活性在分子和细胞水平。白杨素对CBR1的抑制增加了细胞ROS水平并导致ROS依赖性自噬，这导致铁蛋白重链多肽1（FTH1）的降解和参与PC细胞中铁凋亡的细胞内游离铁水平的增加。最后，我们的研究结果表明白杨素增强PC敏感性吉西他滨诱导铁凋亡在体外和体内。总的来说，这些发现表明CBR1是PC治疗的潜在治疗靶点。此外，我们还阐明了白杨素抗肿瘤作用的新机制。
Recent studies have verified that inducing reactive oxygen species (ROS) is one of the gemcitabine anti-tumor mechanisms of action. Human carbonyl reductase 1 (CBR1) plays an important role in protecting cells against oxidative damage. However, it is unclear whether CBR1 is involved in pancreatic cancer (PC) progression and resistance to gemcitabine. Based on the GEPIA database, we analyzed tumor tissue samples from PC patients using immunohistochemistry (IHC) and revealed that CBR1 was highly expressed in PC tissues and that this was significantly correlated with the clinicopathological features of PC. Genetic inhibition of CBR1 suppressed PC cell proliferation by regulating ROS generation. Furthermore, gemcitabine upregulated CBR1 expression, which could limit the anti-tumor activity of gemcitabine, and attenuation of CBR1 enhanced gemcitabine sensitivity in vitro and in vivo. Additionally, we report that chrysin directly binds to CBR1, which inhibited its enzymatic activity both at the molecular and cellular levels. Inhibition of CBR1 by chrysin increased cellular ROS levels and led to ROS-dependent autophagy, which resulted in the degradation of ferritin heavy polypeptide 1 (FTH1) and an increase in the intracellular free iron level that participates in ferroptosis in PC cells. Finally, our results showed that chrysin enhanced PC sensitivity to gemcitabine by inducing ferroptotic death in vitro and in vivo. Collectively, these findings indicate that CBR1 is a potential therapeutic target for PC treatment. In addition, we elucidated a novel mechanism underlying the anti-tumor effects of chrysin.