Lysosomal nitric oxide determines transition from autophagy to ferroptosis after exposure to plasma-activated Ringer's lactate

Redox Biology

Masaaki Mizuno¹  Kenji Ishikawa²  Kotaro Sato³  Hiroaki Kajiyama⁴  Masaru Hori⁴  Hiromasa Tanaka⁵  Shinya Toyokuni⁵  Hao Zheng⁶  Shotaro Hayashi⁶  Yoshitaka Sekido⁶  Li Jiang⁶  Qinying Lyu⁶  Kae Nakamura⁷ 

[1]Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

[2]Center for Low Temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan

[3]Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

[4]Center for Low Temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan

[5]Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

[6]Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

[7]Division of Cancer Biology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan

关键词: Ferroptosis;    Non-thermal plasma-activated Ringer's lactate;    Malignant mesothelioma;    Nitric oxide;    Autophagy;   

DOI  :  

来源: DOAJ

【 摘 要 】

Non-thermal plasma (NTP), an engineered technology to generate reactive species, induces ferroptosis and/or apoptosis specifically in various-type cancer cells. NTP-activated Ringer's lactate (PAL) is another modality for cancer therapy at preclinical stage. Here we found that PAL induces selective ferroptosis of malignant mesothelioma (MM) cells, where non-targeted metabolome screening identified upregulated citrulline-nitric oxide (.NO) cycle as a PAL target. .NO probe detected biphasic peaks transiently at PAL exposure with time-dependent increase, which was responsible for inducible . NO synthase (iNOS) overexpression through NF-κB activation. .NO and lipid peroxidation occupied lysosomes as a major compartment with increased TFEB expression. Not only ferrostatin-1 but inhibitors for . NO and/or iNOS could suppress this ferroptosis. PAL-induced ferroptosis accompanied autophagic process in the early phase, as demonstrated by an increase in essential amino acids, LC3B-II, p62 and LAMP1, transforming into the later phase with boosted lipid peroxidation. Therefore, .NO-mediated lysosomal impairment is central in PAL-induced ferroptosis.

【 授权许可】

Unknown