Theranostics 2021; 11(10):4672-4687. doi:10.7150/thno.54793 This issue

Research Paper

Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy

Szu-Jung Chen1, Li-Hsien Chen1, Yu-Min Yeh1, Chou-Ching K Lin2, Peng-Chan Lin1, Han-Wei Huang2, Meng-Ru Shen3,4, Bo-Wen Lin5, Jeng-Chang Lee5, Cheng-Che Lee6, Yueh-Feng Lee1, Huai-Chueh Chiang1, Jang-Yang Chang1,7,8✉

1. Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
2. Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
3. Department of Obstetrics/Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
4. Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan. Taiwan.
5. Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
6. School of Medicine for International students, College of Medicine, I-SHOU University, Kaohsiung, Taiwan.
7. National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
8. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.

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Citation:
Chen SJ, Chen LH, Yeh YM, Lin CCK, Lin PC, Huang HW, Shen MR, Lin BW, Lee JC, Lee CC, Lee YF, Chiang HC, Chang JY. Targeting lysosomal cysteine protease cathepsin S reveals immunomodulatory therapeutic strategy for oxaliplatin-induced peripheral neuropathy. Theranostics 2021; 11(10):4672-4687. doi:10.7150/thno.54793. Available from https://www.thno.org/v11p4672.htm

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Abstract

Graphic abstract

Rationale: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse effect that causes delayed treatment and poor prognosis among colorectal cancer (CRC) patients. However, its mechanism remains elusive, and no effective treatment is available.

Methods: We employed a prospective cohort study of adult patients with pathologically confirmed stage III CRC receiving adjuvant chemotherapy with an oxaliplatin-based regimen for investigating OIPN. To further validate the clinical manifestations and identify a potential therapeutic strategy, animal models, and in vitro studies on the mechanism of OIPN were applied.

Results: Our work found that (1) consistent with clinical findings, OIPN was observed in animal models. Targeting the enzymatic activity of cathepsin S (CTSS) by pharmacological blockade and gene deficiency strategy alleviates the manifestations of OIPN. (2) Oxaliplatin treatment increases CTSS expression by enhancing cytosol translocation of interferon response factor 1 (IRF1), which then facilitates STIM-dependent store-operated Ca2+ entry homeostasis. (3) The cytokine array demonstrated an increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines in mice treated with RJW-58. (4) Mechanistically, inhibiting CTSS facilitated olfactory receptors transcription factor 1 release from P300/CBP binding, which enhanced binding to the interleukin-10 (IL-10) promoter region, driving IL-10 downstream signaling pathway. (5) Serum CTSS expression is increased in CRC patients with oxaliplatin-induced neurotoxicity.

Conclusions: We highlighted the critical role of CTSS in OIPN, which provides a therapeutic strategy for the common adverse side effects of oxaliplatin.

Keywords: Oxaliplatin-induced peripheral neuropathy, Cathepsin S, olfactory receptor transcription factor 1, IL-10