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  3. Pharmacological inhibition of MELK restricts ferroptosis and the inflammatory response in colitis and colitis-propelled carcinogenesis

Pharmacological inhibition of MELK restricts ferroptosis and the inflammatory response in colitis and colitis-propelled carcinogenesis

  • Free Radic Biol Med. 2021 Aug 20;172:312-329. doi: 10.1016/j.freeradbiomed.2021.06.012.
Bufu Tang 1,  Jinyu Zhu 2,  Shiji Fang 3,  Yajie Wang 4,  Rajamanickam Vinothkumar 5,  Mengyao Li 6,  Qiaoyou Weng 3,  Liyun Zheng 3,  Yang Yang 4,  Rongfang Qiu 4,  Min Xu 4,  Zhongwei Zhao 7,  Jiansong Ji 8
Affiliations

Affiliations

  • 1 Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, China; Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
  • 2 Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, China; Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 3 Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.
  • 4 Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, China; Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.
  • 5 Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, China.
  • 6 School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310016, China.
  • 7 Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, China; Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China. Electronic address: zhaozw79@163.com.
  • 8 Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, China; Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China. Electronic address: jijiansong@zju.edu.cn.
PMID: 34144192 DOI: 10.1016/j.freeradbiomed.2021.06.012
Abstract

Introduction: Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic recurrent and incurable gastrointestinal diseases with an unknown etiology that leads to a high risk of developing colitis-associated colorectal Cancer (CRC).

Objectives: In this study, we measured the expression characteristics of MELK in IBD and CRC tissues and explored the regulatory effect of OTSSP167 (a MELK-selective inhibitor) on the mice models of colitis and colitis-associated carcinogenesis and analyzed the specific molecular mechanisms.

Methods: DSS-induced colitis and colitis-associated carcinogenesis (CAC) model were treated with MELK Inhibitor OTSSP167 then the fight against effect of OTSSP167 in the clinical symptoms of colitis and CAC was measured. In addition, underlying mechanism of OTSSP167 treatment in vitro and vivo including anti-ferroptosis and anti-inflammatory response effect was further explored.

Results: We found that pharmacological inhibition of MELK was indicated to significantly alleviate the inflammatory response in mice with colitis, reduce intestinal damage, and effectively inhibit the occurrence and progression of colitis-propelled carcinogenesis, which was closely related to the regulation of gut microbial composition, and OTSSP167-mediated fecal microbiota transplantation effectively alleviated DSS-induced colitis. In addition, OTSSP167 treatment obviously inhibited Ferroptosis in the intestinal tissue and suppressed macrophage infiltration and M1 polarization, which reduced the secretion of pro-inflammatory factors. Further exploration of the molecular mechanism revealed that OTSSP167 inhibited Akt/IKK/P65 and ERK/IKK/P65 signaling cascades both in vivo and in vitro, which may help alleviate intestinal inflammation and control the occurrence of Cancer.

Conclusion: Our findings lay a theoretical foundation for the use of OTSSP167 as a treatment for IBD and its inhibition of the occurrence of colitis-associated carcinogenesis; additionally, MELK may be a potentially effective target molecule, thus providing more options for clinical treatment.

Keywords

Ferroptosis; Gut microbial; Inflammation; MELK; OTSSP167.

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