<br>低温血浆和低浓度 RSL3 协同作用，通过 ROS/AMPK/mTOR 轴促进肺癌细胞中 xCT 溶酶体降解，从而引发铁死亡,Cell Communication and Signaling

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低温血浆和低浓度 RSL3 协同作用，通过 ROS/AMPK/mTOR 轴促进肺癌细胞中 xCT 溶酶体降解，从而引发铁死亡
Cell Communication and Signaling ( IF 8.2 ) Pub Date : 2024-02-12 , DOI: 10.1186/s12964-023-01382-z
Shengjie Peng _{1,

2} , Guodong Chen _{1,

3} , K N Yu _{4,

5} , Yue Feng _{1,

6} , Lele Zhao _{1,

6} , Miaomiao Yang _{1,

2} , Wei Cao _{1,

2} , Waleed Abdelbagi Ahmed Almahi _{1,

2} , Mingyu Sun _{1,

6} , Yuan Xu _{1,

2} , Ye Zhao ₆ , Cheng Cheng ₇ , Fengqin Zhu ₃ , Wei Han _{1,

3,

6,

8}

Affiliation

Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China.
University of Science and Technology of China, Hefei, 230026, People's Republic of China.
Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China.
Department of Physics, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong, Hong Kong, People's Republic of China.
State Key Laboratory in Marine Pollution, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong, Hong Kong, People's Republic of China.
Teaching and Research Section of Nuclear Medicine, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, People's Republic of China.
Institute of Plasma Physics, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People's Republic of China.
Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Suzhou, 215006, People's Republic of China.

虽然(1S,3R)-RSL3作为铁死亡的小分子诱导剂已广泛应用于基础研究，但RSL3对正常细胞的毒性和较差的药代动力学特性限制了其临床应用。在这里，我们研究了非热等离子体（NTP）和低浓度RSL3的协同作用，并试图提高NSCLC细胞对RSL3的敏感性。采用CCK-8法检测细胞活力的变化。应用显微镜和流式细胞术分别鉴定脂质过氧化、细胞死亡和活性氧（ROS）水平。通过蛋白质印迹和RT-qPCR检查其分子机制。采用异种移植小鼠模型来研究NTP和RSL3的作用。我们发现 NTP 和低浓度 RSL3 的协同作用在体外和体内引发严重的线粒体损伤、更多的细胞死亡和快速的铁死亡。 NTP 和 RSL3 通过 ROS/AMPK/mTOR 信号协同诱导 xCT 溶酶体降解。此外，我们发现线粒体 ROS 是联合治疗诱导的铁死亡的主要执行者。我们的研究表明NTP治疗通过快速诱导更多的铁死亡而促进RSL3的毒性作用，为RSL3的临床应用提供了可能性。

"点击查看英文标题和摘要"

Synergism of non-thermal plasma and low concentration RSL3 triggers ferroptosis via promoting xCT lysosomal degradation through ROS/AMPK/mTOR axis in lung cancer cells

Though (1S, 3R)-RSL3 has been used widely in basic research as a small molecular inducer of ferroptosis, the toxicity on normal cells and poor pharmacokinetic properties of RSL3 limited its clinical application. Here, we investigated the synergism of non-thermal plasma (NTP) and low-concentration RSL3 and attempted to rise the sensitivity of NSCLC cells on RSL3. CCK-8 assay was employed to detect the change of cell viability. Microscopy and flowcytometry were applied to identify lipid peroxidation, cell death and reactive oxygen species (ROS) level respectively. The molecular mechanism was inspected with western blot and RT-qPCR. A xenograft mice model was adopted to investigate the effect of NTP and RSL3. We found the synergism of NTP and low-concentration RSL3 triggered severe mitochondria damage, more cell death and rapid ferroptosis occurrence in vitro and in vivo. NTP and RSL3 synergistically induced xCT lysosomal degradation through ROS/AMPK/mTOR signaling. Furthermore, we revealed mitochondrial ROS was the main executor for ferroptosis induced by the combined treatment. Our research shows NTP treatment promoted the toxic effect of RSL3 by inducing more ferroptosis rapidly and provided possibility of RSL3 clinical application.

更新日期：2024-02-12

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