2. Academic Validation
  3. Elaborate cooperation of poly(rC)-binding proteins 1/2 and glutathione in ferroptosis induced by plasma-activated Ringer's lactate

Elaborate cooperation of poly(rC)-binding proteins 1/2 and glutathione in ferroptosis induced by plasma-activated Ringer's lactate

  • Free Radic Biol Med. 2024 Mar:214:28-41. doi: 10.1016/j.freeradbiomed.2024.02.001.
Li Jiang 1,  Hao Zheng 1,  Moe Ishida 1,  Qinying Lyu 1,  Shinya Akatsuka 1,  Yashiro Motooka 1,  Kotaro Sato 2,  Yoshitaka Sekido 3,  Kae Nakamura 4,  Hiromasa Tanaka 5,  Kenji Ishikawa 6,  Hiroaki Kajiyama 4,  Masaaki Mizuno 7,  Masaru Hori 6,  Shinya Toyokuni 8
Affiliations

Affiliations

  • 1 Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
  • 2 Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan; Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-Ku, Nagoya, 466-8550, Japan.
  • 3 Division of Cancer Biology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.
  • 4 Center for Low-temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya, 464-8603, Japan; Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-Ku, Nagoya, 466-8550, Japan.
  • 5 Center for Low-temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya, 464-8603, Japan; Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, 65 Tsurumai-cho, Showa-Ku, Nagoya, 466-8550, Japan.
  • 6 Center for Low-temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya, 464-8603, Japan.
  • 7 Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, 65 Tsurumai-cho, Showa-Ku, Nagoya, 466-8550, Japan.
  • 8 Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan; Center for Low-temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya, 464-8603, Japan; Center for Integrated Sciences of Low-temperature Plasma Core Research (iPlasma Core), Tokai National Higher Education and Research System, Furo-Cho, Chikusa-ku, Nagoya, 464-8603, Japan. Electronic address: toyokuni@med.nagoya-u.ac.jp.
PMID: 38325565 DOI: 10.1016/j.freeradbiomed.2024.02.001
Abstract

Reactive species are involved in various aspects of neoplastic diseases, including carcinogenesis, cancer-specific metabolism and therapeutics. Non-thermal plasma (NTP) can directly provide reactive species, by integrating atmospheric and interjacent molecules as substrates, to represent a handy strategy to load oxidative stress in situ. NTP causes Apoptosis and/or Ferroptosis specifically in Cancer cells of various types. Plasma-activated Ringer's lactate (PAL) is another modality at the preclinical stage as Cancer therapeutics, based on more stable reactive species. PAL specifically kills malignant mesothelioma (MM) cells, employing lysosomal ·NO as a switch from Autophagy to Ferroptosis. However, the entire molecular mechanisms have not been elucidated yet. Here we studied cytosolic iron regulations in MM and other Cancer cells in response to PAL exposure. We discovered that cells with higher catalytic Fe(II) are more susceptible to PAL-induced Ferroptosis. PAL caused a cytosolic catalytic Fe(II)-associated pathology through iron chaperones, poly (rC)-binding proteins (PCBP)1/2, inducing a disturbance in glutathione-regulated iron homeostasis. PCBP1/NCOA4-mediated ferritinophagy started at a later phase, further increasing cytosolic catalytic Fe(II), ending in Ferroptosis. In contrast, PCBP2 after PAL exposure contributed to iron loading to mitochondria, leading to mitochondrial dysfunction. Therapeutic effect of PAL was successfully applied to an orthotopic MM xenograft model in mice. In conclusion, PAL can selectively sensitize MM cells to Ferroptosis by remodeling cytoplasmic iron homeostasis, where glutathione and PCBPs play distinct roles, resulting in lethal ferritinophagy and mitochondrial dysfunction. Our findings indicate the clinical application of PAL as a ferroptosis-inducer and the potential of PCBPs as novel targets in Cancer therapeutics.

Keywords

Catalytic Fe(II); Ferritinophagy; Ferroptosis; Malignant mesothelioma; Non-thermal plasma; Plasma-activated Ringer's lactate; poly(rC)-binding proteins.

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