Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.
Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.
Int J Biochem Cell Biol. 2021 May;134:105948. doi: 10.1016/j.biocel.2021.105948. Epub 2021 Feb 17.
Ferroptosis, a newly iron-dependent form of cell death, is often accompanied by the damage of membrane lipid peroxide. Recently, the ferroptosis inducer erastin has been reported to exhibit potential anti-cancer activities. The aim of this study was to investigate the effects of SRSF9 on the sensitivity of colorectal cancer (CRC) to erastin and explore the underlying molecular mechanism. Short hairpin RNAs (shRNAs) or SRSF9 overexpression vector (SRSF9-OE) was transfected into erastin-induced human CRC cells to inhibit or overexpress SRSF9. Results showed that SRSF9 inhibition promoted the cell death induced by erastin, conversely, SRSF9 overexpression augmented the resistance to erastin-induced death in human CRC cells. SRSF9 decreased lipid peroxide damage which was a key event during erastin-induced ferroptosis in human CRC cells. Furthermore, we found that SRSF9 inhibition increased erastin-induced ferroptosis by downregulating GPX4 level. In an In vivo study, SRSF9 shRNA or SRSF9-OE stably transfected human CRC cells were subcutaneously injected into the right flank of nude mice. SRSF9 overexpression partly abolished the tumor growth inhibition and ferroptosis induced by erastin. Our data indicated SRSF9's regulation of GPX4 as an essential mechanism driving CRC tumorigenesis and resistance of erastin-induced ferroptosis. This molecular mechanism may provide a novel method for improving the sensitivity of CRC to erastin.
铁死亡是一种新的依赖铁的细胞死亡形式，常伴有膜脂质过氧化物的损伤。最近，铁死亡诱导剂 erastin 被报道具有潜在的抗癌活性。本研究旨在探讨 SRSF9 对结直肠癌（CRC）对 erastin 敏感性的影响，并探讨其潜在的分子机制。短发夹 RNA（shRNA）或 SRSF9 过表达载体（SRSF9-OE）转染到 erastin 诱导的人 CRC 细胞中，以抑制或过表达 SRSF9。结果表明，SRSF9 抑制促进了 erastin 诱导的细胞死亡，相反，SRSF9 过表达增强了人 CRC 细胞对 erastin 诱导死亡的抵抗能力。SRSF9 减少了脂质过氧化物损伤，这是 erastin 诱导铁死亡过程中的一个关键事件。此外，我们发现 SRSF9 抑制通过下调 GPX4 水平增加 erastin 诱导的铁死亡。在体内研究中，SRSF9 shRNA 或 SRSF9-OE 稳定转染的人 CRC 细胞被皮下注射到裸鼠右侧。SRSF9 过表达部分消除了 erastin 诱导的肿瘤生长抑制和铁死亡。我们的数据表明，SRSF9 对 GPX4 的调节是驱动 CRC 肿瘤发生和 erastin 诱导铁死亡抵抗的重要机制。这一分子机制可能为提高 CRC 对 erastin 的敏感性提供一种新方法。
