Frontiers in Pharmacology (Oct 2022)
MLN2238 exerts its anti-tumor effects via regulating ROS/JNK/mitochondrial signaling pathways in intrahepatic cholangiocarcinoma
- Hao Xu,
- Hao Xu,
- Hao Xu,
- Hao Xu,
- Hao Xu,
- Hao Xu,
- Guangyu Xu,
- Guangyu Xu,
- Guangyu Xu,
- Guangyu Xu,
- Guangyu Xu,
- Guangyu Xu,
- Qianhui Xu,
- Qianhui Xu,
- Qianhui Xu,
- Qianhui Xu,
- Qianhui Xu,
- Qianhui Xu,
- Chang Xu,
- Chang Xu,
- Chang Xu,
- Chang Xu,
- Chang Xu,
- Chang Xu,
- Xiaohu Zhou,
- Yang Bai,
- Yang Bai,
- Yang Bai,
- Yang Bai,
- Yang Bai,
- Yang Bai,
- Lu Yin,
- Yuan Ding,
- Yuan Ding,
- Yuan Ding,
- Yuan Ding,
- Yuan Ding,
- Yuan Ding,
- Weilin Wang,
- Weilin Wang,
- Weilin Wang,
- Weilin Wang,
- Weilin Wang,
- Weilin Wang
Affiliations
- Hao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Hao Xu
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- Hao Xu
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China
- Hao Xu
- Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China
- Hao Xu
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Hao Xu
- Cancer Center, Zhejiang University, Hangzhou, China
- Guangyu Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Guangyu Xu
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- Guangyu Xu
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China
- Guangyu Xu
- Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China
- Guangyu Xu
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Guangyu Xu
- Cancer Center, Zhejiang University, Hangzhou, China
- Qianhui Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Qianhui Xu
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- Qianhui Xu
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China
- Qianhui Xu
- Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China
- Qianhui Xu
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Qianhui Xu
- Cancer Center, Zhejiang University, Hangzhou, China
- Chang Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Chang Xu
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- Chang Xu
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China
- Chang Xu
- Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China
- Chang Xu
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Chang Xu
- Cancer Center, Zhejiang University, Hangzhou, China
- Xiaohu Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Yang Bai
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Yang Bai
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- Yang Bai
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China
- Yang Bai
- Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China
- Yang Bai
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Yang Bai
- Cancer Center, Zhejiang University, Hangzhou, China
- Lu Yin
- Department of Pathology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Yuan Ding
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Yuan Ding
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- Yuan Ding
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China
- Yuan Ding
- Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China
- Yuan Ding
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Yuan Ding
- Cancer Center, Zhejiang University, Hangzhou, China
- Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Weilin Wang
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- Weilin Wang
- Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou, China
- Weilin Wang
- Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University, Hangzhou, China
- Weilin Wang
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Weilin Wang
- Cancer Center, Zhejiang University, Hangzhou, China
- DOI
- https://doi.org/10.3389/fphar.2022.1040847
- Journal volume & issue
-
Vol. 13
Abstract
Background: Intrahepatic Cholangiocarcinoma (iCCA) is a highly malignant tumor with limited treatment options that contributes largely to cancer-related deaths worldwide. Compared with traditional transcriptomic analysis, single-cell RNA sequencing (scRNA-seq) is emerging as a more advanced and popular tool for the in-depth exploration of cellular diversity and molecular complexity. As a next-generation proteasome inhibitor, MLN2238 presents better pharmacodynamics, pharmacokinetics, and therapeutic responses in various cancers. However, its effects and mechanisms of action in iCCA remain unknown.Methods: iCCA tumor heterogeneity was determined based on 4,239 qualified scRNA-seq data from 10 iCCA samples. The potential biological roles of proteasome-related genes in iCCA were investigated using a pseudo-trajectory reconstruction. The effect of MLN2238 on iCCA cell proliferation was estimated using the CCK-8, EdU, and clone formation assays. Flow cytometry was used to examine the effect of added MLN2238 on cell cycle and apoptosis levels. Autophagic flux was detected using AdPlus-mCherry-GFP-LC3B cells. ROS levels and mitochondrial membrane potential were determined using DCFH-DA probing and JC-1 staining. JNK activation and mitochondrial apoptosis were observed using western blotting and immunofluorescence microscopy, respectively. Finally, we used a tumor-bearing mouse model to validate its efficacy in vivo for iCCA treatment.Results: Proteasome-related genes were dysregulated in iCCA progression and expressed at higher levels in tumor tissues. MLN2238 suppressed cell proliferation, blocked the cell cycle in the G2/M phase, promoted apoptosis, and induced cytoprotective autophagy in iCCA cells. Furthermore, MLN2238 increased ROS levels and activated the JNK signaling pathway. Inhibition of ROS and JNK activation by NAC and SP600125 significantly reversed MLN2238-induced apoptosis. MLN2238 also suppressed the growth of iCCA tumors in vivo.Conclusion: Proteasome-related genes play pivotal roles in iCCA development. MLN2238, as a proteasome inhibitor, induces apoptosis in iCCA cells through ROS/JNK/mitochondrial signaling pathways, and hence, making MLN2238 a potential therapeutic choice for iCCA.
Keywords
- intrahepatic cholangiocarcinoma
- proteasome inhibitors
- autophagy
- apoptosis
- ROS/JNK/mitochondrial signaling pathway