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Xie Q, He Z, Tan L, Li M, Zhuang M, Liu C, Chen S, Jin L, Sui Y. Hesperetin induces apoptosis in lung squamous carcinoma cells via G 2/M cycle arrest, inhibition of the Notch1 pathway and activation of endoplasmic reticulum stress. Int J Mol Med 2025; 55:77. [PMID: 40084686 PMCID: PMC11936485 DOI: 10.3892/ijmm.2025.5518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 02/20/2025] [Indexed: 03/16/2025] Open
Abstract
Hesperetin (HST), a natural flavonoid, has potent antitumor effects on lung adenocarcinoma; however, its effects on lung squamous cell carcinoma (LUSC) are currently unknown. The present study aimed to investigate the anticancer effects of HST on LUSC cells. The influence of 37.5, 75 and 150 µM HST on the H1703 cell line, and of 75, 150 and 300 µM HST on the H226 cell line was determined using the Cell Counting Kit‑8 method, cell cycle assay, JC‑1 mitochondrial membrane potential assay and Annexin V‑FITC/PI staining. DMSO‑treated cells were used as the control group. Western blotting was performed to detect the protein expression levels of cyclin B1, CDK1, Bcl‑2, Bax, caspase‑3, cleaved caspase‑3, phosphorylated‑eIF2α, eIF2α, glucose‑regulated protein 78, CHOP, Notch1 and Hes‑1. The relationship between endoplasmic reticulum stress (ERS), Notch1 signaling and apoptosis was examined using the ERS‑inhibitor 4‑phenylbutyric acid (4‑PBA; 500 µM) and the Notch1 signaling activator Jagged‑1 (4 µM). In vivo, mice were divided into control, HST (30, 60 and 90 mg/kg/q2d) and cisplatin (2 mg/kg/q2d) groups to evaluate the anti‑LUSC effects of HST. The results revealed that HST inhibited the viability of H226 and H1703 cells, leading to cell cycle arrest at the G2/M phase and the induction of cell apoptosis. In addition, HST downregulated the Notch1 signaling pathway and increased ERS. In H1703 cells, 4‑PBA and Jagged‑1 reduced the expression of apoptosis‑related proteins, and Jagged‑1 also reduced the expression of ERS‑related proteins. In vivo, HST reduced tumor growth without any apparent toxic side effects. In conclusion, HST may exert its antitumor effects by inducing G2/M cell cycle arrest and inhibiting the Notch1 signaling pathway to activate ERS‑induced apoptosis, making it a promising agent for treating LUSC.
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Affiliation(s)
- Qianlong Xie
- Department of Pharmacy, Wuping County Hospital, Longyan, Fujian 363400, P.R. China
- School of Pharmacy, Fujian Medical University, Fuzhou, Fujian 350122, China
| | - Ziming He
- School of Pharmacy, Fujian Medical University, Fuzhou, Fujian 350122, China
| | - Lingfang Tan
- School of Pharmacy, Fujian Medical University, Fuzhou, Fujian 350122, China
| | - Min Li
- Department of Clinical Laboratory, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Min Zhuang
- School of Pharmacy, Fujian Medical University, Fuzhou, Fujian 350122, China
| | - Chen Liu
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350122, P.R. China
| | - Sunhui Chen
- Department of Pharmacy, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
- Department of Pharmacy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Long Jin
- Department of Pathology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
- Department of Pathology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Yuxia Sui
- Department of Pharmacy, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
- Department of Pharmacy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
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Hu L, Lu J, Fan H, Niu C, Han Y, Caiyin Q, Wu H, Qiao J. FAS mediates apoptosis, inflammation, and treatment of pathogen infection. Front Cell Infect Microbiol 2025; 15:1561102. [PMID: 40330016 PMCID: PMC12052831 DOI: 10.3389/fcimb.2025.1561102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 03/25/2025] [Indexed: 05/08/2025] Open
Abstract
The FAS cell surface death receptor, a member of the tumor necrosis factor receptor family, activates both apoptotic and non-apoptotic signaling upon interaction with its ligand FASL. It is critical in cell migration, invasion, immune responses, and carcinogenesis. Pathogen infection can influence host cells' behavior by modulating the FAS/FASL pathway, thereby influencing disease progression. Understanding the role of FAS signaling in the context of pathogen interactions is therefore crucial. This review examines FAS-mediated apoptotic and non-apoptotic signaling pathways, with particular emphasis on the mechanisms of apoptosis and inflammation induced by bacterial and viral infections. Additionally, it highlights therapeutic strategies, including drug, cytokine, antibody, and FASL recombinant protein therapies, providing new directions for treating pathogenic infections and cancers, as well as insights into developing novel therapeutic approaches.
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Affiliation(s)
- Liying Hu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
| | - Juane Lu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
| | - Hongfei Fan
- Tianjin Key Laboratory of Food Science and Biotechnology, College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China
| | - Changcheng Niu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
| | - Yanping Han
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
| | - Qinggele Caiyin
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin, China
- State Key Laboratory of Synthetic Biology, Tianjin University, Tianjin, China
| | - Hao Wu
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
| | - Jianjun Qiao
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin, China
- State Key Laboratory of Synthetic Biology, Tianjin University, Tianjin, China
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Wang PX, Zhu L, Xiang M, Zhang R, Zheng X, Zheng Z, Li K. FTO Alleviates Hepatic Ischemia-Reperfusion Injury by Regulating Apoptosis and Autophagy. Gastroenterol Res Pract 2025; 2025:5587859. [PMID: 39811145 PMCID: PMC11730018 DOI: 10.1155/grp/5587859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 10/07/2024] [Accepted: 12/20/2024] [Indexed: 01/16/2025] Open
Abstract
Objective: Despite N6-methyladenosine (m6A) being closely involved in various pathophysiological processes, its potential role in liver injury is largely unknown. We designed the current research to study the potential role of fat mass and obesity-associated protein (FTO), an m6A demethylase, on hepatic ischemia-reperfusion injury (IRI). Methods: Wild-type mice injected with an adeno-associated virus carrying fat mass and obesity-associated protein (AAV-FTO) or adeno-associated virus carrying green fluorescent protein (GFP) (AAV-GFP) were subjected to a hepatic IRI model in vivo. Hematoxylin-eosin staining was performed to observe IRI. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to observe the cell apoptosis. Reverse transcription polymerase chain reaction (RT-PCR) was used to observe the expression of FTO. The protein levels of FTO, apoptosis, or autophagy-associated signaling proteins were detected by western blot. Reactive oxygen species (ROS) levels were determined by flow cytometry, and immunohistochemistry was used to detect the FTO and LC3-II expression. For in vitro experiments, cultured hepatocytes were subjected to hypoxia/reoxygenation (H/R) stimulation. Monodansylcadaverine (MDC) staining was used to visualize autophagic vesicles. Results: In the present study, we showed that FTO was involved in hepatic IRI, apoptosis, and autophagy. Specifically, the expression level of FTO was significantly reduced in the hepatic IRI. Besides, increasing FTO expression (AAV-FTO) ameliorated the hepatic IRI in animal models, accompanied by decreased apoptosis and autophagy. Furthermore, the FTO inhibitor (FB23-2) aggravated autophagy in hepatocytes upon H/R-induced damage. Conclusion: FTO could act as a protective effector during hepatic IRI, associated with decreased apoptosis and autophagy. FTO-mediated m6A demethylation modification may be an important therapeutic target for hepatic IRI.
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Affiliation(s)
- Pi-Xiao Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mei Xiang
- Department of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rixin Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaolin Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Li
- Department of Hepatobiliary and Pancreatic Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Tayal R, Mannan A, Singh S, Dhiman S, Singh TG. Unveiling the Complexities: Exploring Mechanisms of Anthracyclineinduced Cardiotoxicity. Curr Cardiol Rev 2025; 21:42-77. [PMID: 39484769 PMCID: PMC12060933 DOI: 10.2174/011573403x322928241021100631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 08/27/2024] [Accepted: 08/27/2024] [Indexed: 11/03/2024] Open
Abstract
The coexistence of cancer and heart disease, both prominent causes of illness and death, is further exacerbated by the detrimental impact of chemotherapy. Anthracycline-induced cardiotoxicity is an unfortunate side effect of highly effective therapy in treating different types of cancer; it presents a significant challenge for both clinicians and patients due to the considerable risk of cardiotoxicity. Despite significant progress in understanding these mechanisms, challenges persist in identifying effective preventive and therapeutic strategies, rendering it a subject of continued research even after three decades of intensive global investigation. The molecular targets and signaling pathways explored provide insights for developing targeted therapies, emphasizing the need for continued research to bridge the gap between preclinical understanding and clinical applications. This review provides a comprehensive exploration of the intricate mechanisms underlying anthracycline-induced cardiotoxicity, elucidating the interplay of various signaling pathways leading to adverse cellular events, including cardiotoxicity and death. It highlights the extensive involvement of pathways associated with oxidative stress, inflammation, apoptosis, and cellular stress responses, offering insights into potential and unexplored targets for therapeutic intervention in mitigating anthracycline-induced cardiac complications. A comprehensive understanding of the interplay between anthracyclines and these complexes signaling pathways is crucial for developing strategies to prevent or mitigate the associated cardiotoxicity. Further research is needed to outline the specific contributions of these pathways and identify potential therapeutic targets to improve the safety and efficacy of anthracycline-based cancer treatment. Ultimately, advancements in understanding anthracycline-induced cardiotoxicity mechanisms will facilitate the development of more efficacious preventive and treatment approaches, thereby improving outcomes for cancer patients undergoing anthracycline-based chemotherapy.
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Affiliation(s)
- Rohit Tayal
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Shareen Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Sonia Dhiman
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
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Xie T, Chen Q, Li N, Zhang S, Zhu L, Bai S, Zha H, Tian W, Luo C, Wu N, Zou X, Fang S, Shu Y, Yuan J, Jiang Y, Luo H. RNA-Seq Reveals Transcriptome Changes Following Zika Virus Infection in Fetal Brains in c-Flip Knockdown Mice. Viruses 2024; 16:1712. [PMID: 39599827 PMCID: PMC11599063 DOI: 10.3390/v16111712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 10/19/2024] [Accepted: 10/24/2024] [Indexed: 11/29/2024] Open
Abstract
The FADD-like interleukin-1β converting enzyme (FLICE)-inhibitory protein (c-FLIP) plays a crucial role in various biological processes, including apoptosis and inflammation. However, the complete transcriptional profile altered by the c-FLIP is not fully understood. Furthermore, the impact of the c-FLIP deficiency on the transcriptome during a Zika virus (ZIKV) infection, which induces apoptosis and inflammation in the central nervous system (CNS), has not yet been elucidated. In this study, we compared transcriptome profiles between wild-type (WT) and the c-Flip heterozygous knockout mice (c-Flip+/-) fetal heads at embryonic day 13.5 from control and PBS-infected WT dams mated with c-Flip+/- sires. In the non-infected group, we observed differentially expressed genes (DEGs) mainly involved in embryonic development and neuron development. However, the ZIKV infection significantly altered the transcriptional profile between WT and the c-Flip+/- fetal heads. DEGs in pattern recognition receptor (PRR)-related signaling pathways, such as the RIG-I-like receptor signaling pathway and Toll-like receptor signaling pathway, were enriched. Moreover, the DEGs were also enriched in T cells, indicating that the c-FLIP participates in both innate and adaptive immune responses upon viral infection. Furthermore, our observations indicate that DEGs are associated with sensory organ development and eye development, suggesting a potential role for the c-FLIP in ZIKV-induced organ development defects. Overall, we have provided a comprehensive transcriptional profile for the c-FLIP and its modulation during a ZIKV infection.
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Affiliation(s)
- Ting Xie
- School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China (W.T.); (Y.S.)
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Qiqi Chen
- School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China (W.T.); (Y.S.)
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Nina Li
- School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China (W.T.); (Y.S.)
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
- Key Laboratory of Pathogen Infection Prevention and Control (MOE), State Key Laboratory of Respiratory Health and Multimorbidity, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 102629, China
| | - Shengze Zhang
- School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China (W.T.); (Y.S.)
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Lin Zhu
- School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China (W.T.); (Y.S.)
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Shaohui Bai
- School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China (W.T.); (Y.S.)
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Haolu Zha
- School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China (W.T.); (Y.S.)
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Weijian Tian
- School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China (W.T.); (Y.S.)
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Chuming Luo
- School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China (W.T.); (Y.S.)
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Nan Wu
- Shenzhen Nanshan Center for Disease Control and Prevention, Shenzhen 518054, China
| | - Xuan Zou
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518073, China (J.Y.)
| | - Shisong Fang
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518073, China (J.Y.)
| | - Yuelong Shu
- School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China (W.T.); (Y.S.)
- Key Laboratory of Pathogen Infection Prevention and Control (MOE), State Key Laboratory of Respiratory Health and Multimorbidity, National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 102629, China
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China
| | - Jianhui Yuan
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518073, China (J.Y.)
| | - Ying Jiang
- Shenzhen Nanshan Center for Disease Control and Prevention, Shenzhen 518054, China
| | - Huanle Luo
- School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China (W.T.); (Y.S.)
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China
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Yang CY, Tseng YC, Tu YF, Kuo BJ, Hsu LC, Lien CI, Lin YS, Wang YT, Lu YC, Su TW, Lo YC, Lin SC. Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes. Nat Commun 2024; 15:8974. [PMID: 39419969 PMCID: PMC11487272 DOI: 10.1038/s41467-024-53306-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024] Open
Abstract
cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high levels of cFLIP in achieving their immortality. However, understanding the three-dimensional regulatory mechanism initiated or mediated by elevated levels of cFLIP has been limited by the absence of the atomic coordinates for cFLIP-induced DED complexes. Here we report the crystal plus cryo-EM structures to uncover an unconventional mechanism where cFLIP and procaspase-8 autonomously form a binary tandem DED complex, independent of FADD. This complex gains the ability to recruit FADD, thereby allosterically modulating cFLIP assembly and partially activating caspase-8 for RIPK1 cleavage. Our structure-guided mutagenesis experiments provide critical insights into these regulatory mechanisms, elucidating the resistance to apoptosis and necroptosis in achieving immortality. Finally, this research offers a unified model for the intricate bidirectional hierarchy-based processes using multiprotein helical assembly to govern cell fate decisions.
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Affiliation(s)
- Chao-Yu Yang
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Yi-Chun Tseng
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Yi-Fan Tu
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Bai-Jiun Kuo
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Li-Chung Hsu
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan
- Center of Precision Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan
| | - Chia-I Lien
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan
| | - You-Sheng Lin
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan
| | - Yin-Ting Wang
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Yen-Chen Lu
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Tsung-Wei Su
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Yu-Chih Lo
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan.
| | - Su-Chang Lin
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
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Figueira MI, Carvalho TMA, Macário-Monteiro J, Cardoso HJ, Correia S, Vaz CV, Duarte AP, Socorro S. The Pros and Cons of Estrogens in Prostate Cancer: An Update with a Focus on Phytoestrogens. Biomedicines 2024; 12:1636. [PMID: 39200101 PMCID: PMC11351860 DOI: 10.3390/biomedicines12081636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/14/2024] [Accepted: 07/20/2024] [Indexed: 09/01/2024] Open
Abstract
The role of estrogens in prostate cancer (PCa) is shrouded in mystery, with its actions going from angelic to devilish. The findings by Huggins and Hodges establishing PCa as a hormone-sensitive cancer have provided the basis for using estrogens in therapy. However, despite the clinical efficacy in suppressing tumor growth and the panoply of experimental evidence describing its anticarcinogenic effects, estrogens were abolished from PCa treatment because of the adverse secondary effects. Notwithstanding, research work over the years has continued investigating the effects of estrogens, reporting their pros and cons in prostate carcinogenesis. In contrast with the beneficial therapeutic effects, many reports have implicated estrogens in the disruption of prostate cell fate and tissue homeostasis. On the other hand, epidemiological data demonstrating the lower incidence of PCa in Eastern countries associated with a higher consumption of phytoestrogens support the beneficial role of estrogens in counteracting cancer development. Many studies have investigated the effects of phytoestrogens and the underlying mechanisms of action, which may contribute to developing safe estrogen-based anti-PCa therapies. This review compiles the existing data on the anti- and protumorigenic actions of estrogens and summarizes the anticancer effects of several phytoestrogens, highlighting their promising features in PCa treatment.
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Affiliation(s)
| | | | | | | | | | | | | | - Sílvia Socorro
- CICS-UBI, Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6200-506 Covilhã, Portugal; (M.I.F.)
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8
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Yang CY, Lien CI, Tseng YC, Tu YF, Kulczyk AW, Lu YC, Wang YT, Su TW, Hsu LC, Lo YC, Lin SC. Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis. Nat Commun 2024; 15:3791. [PMID: 38710704 PMCID: PMC11074299 DOI: 10.1038/s41467-024-47990-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 04/17/2024] [Indexed: 05/08/2024] Open
Abstract
Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions. These structures illustrate how FADD and cFLIP orchestrate the assembly of caspase-8-containing complexes and offer mechanistic explanations for their role in promoting or inhibiting apoptotic and necroptotic signaling. A helical procaspase-8-cFLIP hetero-double layer in the complex appears to promote limited caspase-8 activation for cell survival. Our structure-guided mutagenesis supports the role of the triple-FADD complex in caspase-8 activation and in regulating receptor-interacting protein kinase 1 (RIPK1). These results propose a unified mechanism for DED assembly and procaspase-8 activation in the regulation of apoptotic and necroptotic signaling across various cellular pathways involved in development, innate immunity, and disease.
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Grants
- AS-TP-107-L16, AS-TP-107-L16-1, AS-102-TP-B14 and AS-102-TP-B14-2 Academia Sinica
- AS-TP-107-L16-2 and AS-102-TP-B14-1 Academia Sinica
- AS-TP-107-L16-3 Academia Sinica
- MoST 107-2320-B-001-018-, 108-2311-B-001-018-, 109-2311-B-001-016-, and 110-2311-B-001-015- Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
- MoST 107-2320-B-006-062-MY3, and 111-2311-B-006-005-MY3 Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
- MoST 108-2320-B-002-020-MY3, 111-2320-B-002-048-MY3, and 112-2326-B-002-007- Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
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Affiliation(s)
- Chao-Yu Yang
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Chia-I Lien
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan
| | - Yi-Chun Tseng
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Yi-Fan Tu
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Arkadiusz W Kulczyk
- Institute for Quantitative Biomedicine, Rutgers University, Department of Biochemistry and Microbiology, Rutgers University, Piscataway, NJ, 08854, USA
| | - Yen-Chen Lu
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Yin-Ting Wang
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Tsung-Wei Su
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Li-Chung Hsu
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan.
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan.
| | - Yu-Chih Lo
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan.
| | - Su-Chang Lin
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
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9
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Köberle B, Usanova S, Piee-Staffa A, Heinicke U, Clauss P, Brozovic A, Kaina B. Strong apoptotic response of testis tumor cells following cisplatin treatment. Int Urol Nephrol 2024; 56:1007-1017. [PMID: 37891379 PMCID: PMC10853295 DOI: 10.1007/s11255-023-03825-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 09/25/2023] [Indexed: 10/29/2023]
Abstract
Most solid metastatic cancers are resistant to chemotherapy. However, metastatic testicular germ cell tumors (TGCT) are cured in over 80% of patients using cisplatin-based combination therapy. Published data suggest that TGCTs are sensitive to cisplatin due to limited DNA repair and presumably also to a propensity to undergo apoptosis. To further investigate this aspect, cisplatin-induced activation of apoptotic pathways was investigated in cisplatin-sensitive testis tumor cells (TTC) and compared to cisplatin-resistant bladder cancer cells. Apoptosis induction was investigated using flow cytometry, caspase activation and PARP-1 cleavage. Immunoblotting and RT-PCR were applied to investigate pro- and anti-apoptotic proteins. Transfections were performed to target p53- and Fas/FasL-mediated apoptotic signaling. Immunoblotting experiments revealed p53 to be induced in TTC, but not bladder cancer cells following cisplatin. Higher levels of pro-apoptotic Bax and Noxa were observed in TTC, anti-apoptotic Bcl-2 was solely expressed in bladder cancer cells. Cisplatin led to translocation of Bax to the mitochondrial membrane in TTC, resulting in cytochrome C release. Cisplatin increased the expression of FasR mRNA and FasL protein in all tumor cell lines. Targeting the apoptotic pathway via siRNA-mediated knockdown of p53 and FAS reduced death receptor-mediated apoptosis and increased cisplatin resistance in TTC, indicating the involvement of FAS-mediated apoptosis in the cisplatin TTC response. In conclusion, both the death receptor and the mitochondrial apoptotic pathway become strongly activated in TTC following cisplatin treatment, explaining, together with attenuated DNA repair, their unique sensitivity toward platinum-based anticancer drugs.
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Affiliation(s)
- Beate Köberle
- Institute of Toxicology, University of Mainz Medical Center, 55131, Mainz, Germany.
- Department of Food Chemistry and Toxicology, Karlsruhe Institute of Technology, 76131, Karlsruhe, Germany.
| | - Svetlana Usanova
- Institute of Toxicology, University of Mainz Medical Center, 55131, Mainz, Germany
| | - Andrea Piee-Staffa
- Institute of Toxicology, University of Mainz Medical Center, 55131, Mainz, Germany
| | - Ulrike Heinicke
- Institute of Toxicology, University of Mainz Medical Center, 55131, Mainz, Germany
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, 60596, Frankfurt Am Main, Germany
| | - Philipp Clauss
- Institute of Toxicology, University of Mainz Medical Center, 55131, Mainz, Germany
| | - Anamaria Brozovic
- Division of Molecular Biology, Ruđer Bošković Institute, 10000, Zagreb, Croatia
| | - Bernd Kaina
- Institute of Toxicology, University of Mainz Medical Center, 55131, Mainz, Germany.
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10
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Santacroce L, Magrone T. Molluscum Contagiosum Virus: Biology and Immune Response. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1451:151-170. [PMID: 38801577 DOI: 10.1007/978-3-031-57165-7_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Molluscum contagiosum virus is a poxvirus belonging to the Poxviridae family, which includes Orthopoxvirus, Parapoxvirus, Yantapoxvirus, Molluscipoxvirus, Smallpox virus, Cowpox virus and Monkeypox virus. MCV belongs to the genus Molluscipoxvirus and has a tropism for skin tissue. MCV infects keratinocytes and, after an incubation period of 2 weeks to 6 weeks, causes a breakdown of the skin barrier with the development of papules of variable size depending on the proper functioning of the immune response (both adaptive and acquired). MCV only infects humans and does not cause viraemia. MCV encodes for several inhibitory proteins responsible to circumvent the immune response through different signalling pathways. Individuals who can be infected with MCV are children, immunocompromised individuals such as organ transplant recipients and Human Immunodeficiency Virus (HIV)-infected individuals. Current treatments to manage MCV-induced lesions are different and include the use of immunomodulators, which, however, do not provide an effective response.
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Affiliation(s)
- Luigi Santacroce
- Section of Microbiology and Virology, Interdisciplinary Department of Medicine, School of Medicine, University of Bari, Bari, Italy.
| | - Thea Magrone
- Section of Microbiology and Virology, Interdisciplinary Department of Medicine, School of Medicine, University of Bari, Bari, Italy
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11
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Zheng Y, Zhong G, He C, Li M. Targeted splicing therapy: new strategies for colorectal cancer. Front Oncol 2023; 13:1222932. [PMID: 37664052 PMCID: PMC10470845 DOI: 10.3389/fonc.2023.1222932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 08/07/2023] [Indexed: 09/05/2023] Open
Abstract
RNA splicing is the process of forming mature mRNA, which is an essential phase necessary for gene expression and controls many aspects of cell proliferation, survival, and differentiation. Abnormal gene-splicing events are closely related to the development of tumors, and the generation of oncogenic isoform in splicing can promote tumor progression. As a main process of tumor-specific splicing variants, alternative splicing (AS) can promote tumor progression by increasing the production of oncogenic splicing isoforms and/or reducing the production of normal splicing isoforms. This is the focus of current research on the regulation of aberrant tumor splicing. So far, AS has been found to be associated with various aspects of tumor biology, including cell proliferation and invasion, resistance to apoptosis, and sensitivity to different chemotherapeutic drugs. This article will review the abnormal splicing events in colorectal cancer (CRC), especially the tumor-associated splicing variants arising from AS, aiming to offer an insight into CRC-targeted splicing therapy.
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Affiliation(s)
| | | | - Chengcheng He
- Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
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12
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Pimentel JM, Zhou JY, Wu GS. The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer. Cancers (Basel) 2023; 15:2752. [PMID: 37345089 DOI: 10.3390/cancers15102752] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/01/2023] [Accepted: 05/10/2023] [Indexed: 06/23/2023] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that selectively induces apoptosis in tumor cells without harming normal cells, making it an attractive agent for cancer therapy. TRAIL induces apoptosis by binding to and activating its death receptors DR4 and DR5. Several TRAIL-based treatments have been developed, including recombinant forms of TRAIL and its death receptor agonist antibodies, but the efficacy of TRAIL-based therapies in clinical trials is modest. In addition to inducing cancer cell apoptosis, TRAIL is expressed in immune cells and plays a critical role in tumor surveillance. Emerging evidence indicates that the TRAIL pathway may interact with immune checkpoint proteins, including programmed death-ligand 1 (PD-L1), to modulate PD-L1-based tumor immunotherapies. Therefore, understanding the interaction between TRAIL and the immune checkpoint PD-L1 will lead to the development of new strategies to improve TRAIL- and PD-L1-based therapies. This review discusses recent findings on TRAIL-based therapy, resistance, and its involvement in tumor immunosurveillance.
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Affiliation(s)
- Julio M Pimentel
- Molecular Therapeutics Program, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Cancer Biology Program, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Department of Oncology, School of Medicine, Wayne State University, Detroit, MI 48201, USA
| | - Jun-Ying Zhou
- Molecular Therapeutics Program, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Department of Oncology, School of Medicine, Wayne State University, Detroit, MI 48201, USA
| | - Gen Sheng Wu
- Molecular Therapeutics Program, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Cancer Biology Program, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Department of Oncology, School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA
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13
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Kouroumalis E, Tsomidis I, Voumvouraki A. Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy. Biomedicines 2023; 11:1166. [PMID: 37189787 PMCID: PMC10135776 DOI: 10.3390/biomedicines11041166] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete School of Medicine, 71500 Heraklion, Crete, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
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14
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Triptolide-mediated downregulation of FLIP S in hepatoma cells occurs at the post-transcriptional level independently of proteasome-mediated pathways. Med Oncol 2023; 40:7. [PMID: 36308574 PMCID: PMC9617966 DOI: 10.1007/s12032-022-01857-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 09/20/2022] [Indexed: 01/17/2023]
Abstract
Cellular c-FLIP prevents apoptosis mediated by death receptor through inhibiting activation of caspase-8. Therefore, when c-FLIP is downregulated or eliminated, caspase-8 activation is promoted, and death receptor ligand-induced apoptosis is activated. It was reported that triptolide (TPL) sensitized tumor cells to TNF-α-induced apoptosis by blocking TNF-α-induced activation of NF-κB and transcription of c-IAP1 and c-IAP2. However, the effect of TPL on basal c-FLIP expression was not understood. In this study, we found that the combination of TNF-α and TPL accelerated apoptosis in human hepatocellular carcinoma cells and TNF-α-induced elevated as well as basal level of FLIPS protein were downregulated by TPL. Additionally, we demonstrated that the basal level of FLIPS in Huh7 cells was continuously downregulated following the incubation of TPL and downregulated more when dosage of TPL for treatment was increased. Subsequently, we showed that TPL reduced FLIPS level in a transcription- and degradation-independent mechanism. Our findings suggest that TPL induces loss of FLIPS at the post-transcriptional level independently of proteasome-mediated pathway, an additional mechanism of TPL sensitizing cancer cells to TNF-α-induced apoptosis.
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15
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Mechanisms of Drug Resistance in Ovarian Cancer and Associated Gene Targets. Cancers (Basel) 2022; 14:cancers14246246. [PMID: 36551731 PMCID: PMC9777152 DOI: 10.3390/cancers14246246] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/30/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022] Open
Abstract
In the United States, over 100,000 women are diagnosed with a gynecologic malignancy every year, with ovarian cancer being the most lethal. One of the hallmark characteristics of ovarian cancer is the development of resistance to chemotherapeutics. While the exact mechanisms of chemoresistance are poorly understood, it is known that changes at the cellular and molecular level make chemoresistance challenging to treat. Improved therapeutic options are needed to target these changes at the molecular level. Using a precision medicine approach, such as gene therapy, genes can be specifically exploited to resensitize tumors to therapeutics. This review highlights traditional and novel gene targets that can be used to develop new and improved targeted therapies, from drug efflux proteins to ovarian cancer stem cells. The review also addresses the clinical relevance and landscape of the discussed gene targets.
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16
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Kim JH, Najy AJ, Li J, Luo X, Kim HRC, Choudry MHA, Lee YJ. Involvement of Bid in the crosstalk between ferroptotic agent-induced ER stress and TRAIL-induced apoptosis. J Cell Physiol 2022; 237:4180-4196. [PMID: 35994698 PMCID: PMC9691566 DOI: 10.1002/jcp.30863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 08/04/2022] [Accepted: 08/10/2022] [Indexed: 11/10/2022]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces death receptor-mediated extrinsic apoptosis, specifically in cancer cells, and Bid (BH3-interacting domain death agonist) plays an important role in TRAIL-induced apoptosis. Ferroptosis is a newly defined form of regulated cell death known to be distinct from other forms of cell death. However, our previous studies have shown that ferroptosis shares common pathways with other types of programmed cell death such as apoptosis. In this study, we investigated the role of Bid in the crosstalk between the ferroptotic agent-induced endoplasmic reticulum (ER) stress response and TRAIL-induced apoptosis. When human colorectal carcinoma HCT116 cells were treated with the ferroptosis-inducing agents artesunate and erastin in combination with TRAIL, TRAIL-induced activation of caspase-8 was enhanced, and subsequently, the truncation of Bid was increased. Similar results were observed when ovarian adenocarcinoma OVCAR-3 cells were treated with the ferroptotic agents in combination with TRAIL. Results from studies with Bid mutants reveal that the truncation of Bid and the presence of intact BH3 domains are critical for synergistic apoptosis. Nonfunctional Bid mutants were not able to activate the mitochondria-dependent apoptosis pathway, which is required for the conversion of p19 to p17, the active form of caspase-3. These results indicate that Bid plays a critical role in the crosstalk between the ferroptotic agent-induced ER stress response and TRAIL-induced apoptosis.
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Affiliation(s)
- Jin Hong Kim
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Abdo J. Najy
- Department of Pathology, Barbara Ann Karmanos Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
- Department of Oncology, Barbara Ann Karmanos Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Jian Li
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
| | - Xu Luo
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
| | - Hyeong-Reh C. Kim
- Department of Pathology, Barbara Ann Karmanos Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
- Department of Oncology, Barbara Ann Karmanos Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - M. Haroon A. Choudry
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Yong J. Lee
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
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17
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Sun SY. Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors. Front Med 2022; 16:701-713. [PMID: 36152124 DOI: 10.1007/s11684-022-0951-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/28/2022] [Indexed: 11/28/2022]
Abstract
A significant clinical challenge in lung cancer treatment is management of the inevitable acquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib, which have shown remarkable success in the treatment of advanced NSCLC with EGFR activating mutations, in order to achieve maximal response duration or treatment remission. Apoptosis is a major type of programmed cell death tightly associated with cancer development and treatment. Evasion of apoptosis is considered a key hallmark of cancer and acquisition of apoptosis resistance is accordingly a key mechanism of drug acquired resistance in cancer therapy. It has been clearly shown that effective induction of apoptosis is a key mechanism for third generation EGFR-TKIs, particularly osimertinib, to exert their therapeutic efficacies and the development of resistance to apoptosis is tightly associated with the emergence of acquired resistance. Hence, restoration of cell sensitivity to undergo apoptosis using various means promises an effective strategy for the management of acquired resistance to third generation EGFR-TKIs.
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Affiliation(s)
- Shi-Yong Sun
- Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA.
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18
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Jeong MA, Jeong YJ, Kim KI. Virulence difference between red sea bream iridovirus mixed subtype I/II and subtype II and the expression of viral and apoptosis-related genes in infected rock bream (Oplegnathus fasciatus). FISH & SHELLFISH IMMUNOLOGY 2022; 127:195-202. [PMID: 35643355 DOI: 10.1016/j.fsi.2022.05.041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/28/2022] [Accepted: 05/19/2022] [Indexed: 06/15/2023]
Abstract
In this study, the virulence of the red sea bream iridovirus (RSIV) subtype II (17RbGs isolate) and a novel RSIV mixed subtype I/II (17SbTy isolate), which was genetically characterized in a previous study, were compared. The infectivity to rock bream (Oplegnathus fasciatus) determined by infectious dose (ID50) revealed that 17RbGs isolate was significantly more infective than 17SbTy isolate using both intraperitoneal injection and bath immersion. In a cohabitation challenge test that mimicked natural conditions, the cumulative mortality of the donor (RSIV-injected rock bream) and the recipient (cohabited naïve rock bream) was significantly higher in the 17RbGs group than in the 17SbTy group, regardless of RSIV injected doses, supporting the correlation between genetic mutation and pathogenicity. In addition, the maximum viral shedding ratio identified from RSIV-infected rock bream suggested that viral transmission through infection with the 17SbTy isolate could have a lower relative risk than that of infection with the 17RbGs isolate. In particular, the odds ratio based on the spleen index after 17RbGs infection was 55.00, which was inconsistent with that of 17SbTy infection (19.38), hence supporting the virulence difference between RSIVs. Furthermore, the expression of viral genes, including DNA membrane and myristoylated protein genes with insertion and deletion mutations, and that of caspase-8, which is related to caspase-dependent apoptosis induced by RSIV infection, were significantly upregulated at 11 days post 17RbGs-infection compared to that following 17SbTy infection. Notably, although viral genes were highly expressed in the early infection stage and caspase-8 was upregulated, the low caspase-3 expression may have inhibited apoptosis, reflecting the difference in virulence between different RSIV isolates. Several virulence factors, including pathogenicity, viral shedding ratio, odds ratio, and gene expression, support that RSIV mixed subtype I/II may be a less pathogenic RSIV isolate compared with general RSIV subtype II in a natural environment.
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Affiliation(s)
- Min A Jeong
- Department of Aquatic Life Medicine, Pukyong National University, Busan, Republic of Korea
| | - Ye Jin Jeong
- Department of Aquatic Life Medicine, Pukyong National University, Busan, Republic of Korea
| | - Kwang Il Kim
- Department of Aquatic Life Medicine, Pukyong National University, Busan, Republic of Korea.
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19
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Human Gammaherpesvirus 8 Oncogenes Associated with Kaposi’s Sarcoma. Int J Mol Sci 2022; 23:ijms23137203. [PMID: 35806208 PMCID: PMC9266852 DOI: 10.3390/ijms23137203] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 01/01/2023] Open
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human gammaherpesvirus 8 (HHV-8), contains oncogenes and proteins that modulate various cellular functions, including proliferation, differentiation, survival, and apoptosis, and is integral to KSHV infection and oncogenicity. In this review, we describe the most important KSHV genes [ORF 73 (LANA), ORF 72 (vCyclin), ORF 71 or ORFK13 (vFLIP), ORF 74 (vGPCR), ORF 16 (vBcl-2), ORF K2 (vIL-6), ORF K9 (vIRF 1)/ORF K10.5, ORF K10.6 (vIRF 3), ORF K1 (K1), ORF K15 (K15), and ORF 36 (vPK)] that have the potential to induce malignant phenotypic characteristics of Kaposi’s sarcoma. These oncogenes can be explored in prospective studies as future therapeutic targets of Kaposi’s sarcoma.
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20
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Ho HY, Chen PJ, Chuang YC, Lo YS, Lin CC, Hsieh MJ, Chen MK. Picrasidine I Triggers Heme Oxygenase-1-Induced Apoptosis in Nasopharyngeal Carcinoma Cells via ERK and Akt Signaling Pathways. Int J Mol Sci 2022; 23:ijms23116103. [PMID: 35682782 PMCID: PMC9181417 DOI: 10.3390/ijms23116103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 12/16/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) has a higher incidence in Taiwan than worldwide. Although it is a radiosensitive malignancy, cancer recurrence is still high in the advanced stages because of its ability to induce lymph node metastasis. Picrasidine I from Picrasma quassioides has been reported as a potential drug for targeting multiple signaling pathways. The present study aimed to explore the role of picrasidine I in the apoptosis of NPC cells. Our results show that picrasidine I induced cytotoxic effects in NPC cells and caused cell cycle arrest in the sub-G1, S, and G2/M phases. Western blot analysis further demonstrated that the modulation of apoptosis through the extrinsic and intrinsic pathways was involved in picrasidine I-induced cell death. Downregulation of the ERK1/2 and Akt signaling pathways was also found in picrasidine I-induced apoptosis. Additionally, the apoptosis array showed that picrasidine I significantly increased heme oxygenase-1 (HO-1) expression, which could act as a critical molecule in picrasidine I-induced apoptosis in NPC cells. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets also revealed that the HMOX1 mRNA level (HO-1) is lower in patients with head and neck squamous carcinoma (HNSCC) and NPC than in patients without cancer. Our study indicated that picrasidine I exerts anticancer effects in NPC by modulating HO-1 via the ERK and Akt signaling pathways.
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Affiliation(s)
- Hsin-Yu Ho
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; (H.-Y.H.); (Y.-C.C.); (Y.-S.L.); (C.-C.L.)
| | - Ping-Ju Chen
- Department of Dentistry, Changhua Christian Hospital, Changhua 500, Taiwan;
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Yi-Ching Chuang
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; (H.-Y.H.); (Y.-C.C.); (Y.-S.L.); (C.-C.L.)
| | - Yu-Sheng Lo
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; (H.-Y.H.); (Y.-C.C.); (Y.-S.L.); (C.-C.L.)
| | - Chia-Chieh Lin
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; (H.-Y.H.); (Y.-C.C.); (Y.-S.L.); (C.-C.L.)
| | - Ming-Ju Hsieh
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan; (H.-Y.H.); (Y.-C.C.); (Y.-S.L.); (C.-C.L.)
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- Correspondence: (M.-J.H.); (M.-K.C.); Tel.: +886-4-7238595 (M.-J.H. & M.-K.C.); Fax: +886-4-7232942 (M.-J.H. & M.-K.C.)
| | - Mu-Kuan Chen
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua 500, Taiwan
- Correspondence: (M.-J.H.); (M.-K.C.); Tel.: +886-4-7238595 (M.-J.H. & M.-K.C.); Fax: +886-4-7232942 (M.-J.H. & M.-K.C.)
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21
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Guo L, Tang T, Fang D, Gong H, Zhang B, Zhou Y, Zhang L, Yan M. An Insight on the Pathways Involved in Crizotinib and Sunitinib Induced Hepatotoxicity in HepG2 Cells and Animal Model. Front Oncol 2022; 12:749954. [PMID: 35155225 PMCID: PMC8832280 DOI: 10.3389/fonc.2022.749954] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 01/13/2022] [Indexed: 11/22/2022] Open
Abstract
Both crizotinib and sunitinib, novel orally-active multikinase inhibitors, exhibit antitumor activity and extend the survival of patients with a malignant tumor. However, some patients may suffer liver injury that can further limit the clinical use of these drugs, however the mechanisms underlying hepatotoxicity are still to be elucidated. Thus, our study was designed to use HepG2 cells in vitro and the ICR mice model in vivo to investigate the mechanisms of hepatotoxicity induced by crizotinib and sunitinib. Male ICR mice were treated orally with crizotinib (70 mg/kg/day) or sunitinib (7.5 mg/kg/day) for four weeks. The results demonstrated that crizotinib and sunitinib caused cytotoxicity in HepG2 cells and chronic liver injury in mice, which were associated with oxidative stress, apoptosis and/or necrosis. Crizotinib- and sunitinib-induced oxidative stress was accompanied by increasing reactive oxygen species and malondialdehyde levels and decreasing the activity of superoxide dismutase and glutathione peroxidase. Notably, the activation of the Kelch-like ECH-associated protein-1/Nuclear factor erythroid-2 related factor 2 signaling pathway was involved in the process of oxidative stress, and partially protected against oxidative stress. Crizotinib and sunitinib induced apoptosis via the mitochondrial pathway, which was characterized by decreasing Bcl2/Bax ratio to dissipate the mitochondrial membrane potential, and increasing apoptotic markers levels. Moreover, the pan-caspase inhibitor Z-VAD-FMK improved the cell viability and alleviated liver damage, which further indicated the presence of apoptosis. Taken together, this study demonstrated that crizotinib- and sunitinib-caused oxidative stress and apoptosis finally impaired hepatic function, which was strongly supported by the histopathological lesions and markedly increased levels of serum alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase.
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Affiliation(s)
- Lin Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Tingli Tang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Dongmei Fang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.,School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yueyin Zhou
- Orthodontic Department of Xiangya Stomatology Hospital, Central South University, Changsha, China
| | - Leiyi Zhang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
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22
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Chen YY, Liang JJ, Wang DL, Chen JB, Cao JP, Wang Y, Sun CD. Nobiletin as a chemopreventive natural product against cancer, a comprehensive review. Crit Rev Food Sci Nutr 2022; 63:6309-6329. [PMID: 35089821 DOI: 10.1080/10408398.2022.2030297] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
As a leading cause of death, second only to heart disease, cancer has always been one of the burning topics in medical research. When targeting multiple signal pathways in tumorigenesis chemoprevention, using natural or synthetic anti-cancer drugs is a vital strategy to reduce cancer damage. However, toxic effects, multidrug resistance (MDR) as well as cancer stem cells (CSCs) all prominently limited the clinical application of conventional anticancer drugs. With low side effects, strong biological activity, unique mechanism, and wide range of targets, natural products derived from plants are considered significant sources for new drug development. Nobiletin is one of the most attractive compounds, a unique flavonoid primarily isolated from the peel of citrus fruits. Numerous studies in vitro and in vivo have suggested that nobiletin and its derivatives possess the eminent potential to become effective cancer chemoprevention agents through various cellular and molecular levels. This article aims to comprehensively review the anticancer efficacy and specific mechanisms of nobiletin, enhancing our understanding of its chemoprevention properties and providing the latest research findings. At the end of this review, we also give some discussion and future perspectives regarding the challenges and opportunities in nobiletin efficient exploitation.
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Affiliation(s)
- Yun-Yi Chen
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
| | - Jiao-Jiao Liang
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
| | - Deng-Liang Wang
- Citrus Research Institute, Quzhou Academy of Agricultural Sciences, Quzhou, China
| | - Jie-Biao Chen
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
| | - Jin-Ping Cao
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
| | - Yue Wang
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
| | - Chong-De Sun
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, China
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23
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Chang Z, Dang T, Meng X, Chai J. The Role of CCN1 in Esophageal Adenocarcinoma: What We Have Learned From the Lab. Cancer Control 2022; 29:10732748221074734. [PMID: 35291889 PMCID: PMC8935545 DOI: 10.1177/10732748221074734] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background: Esophageal cancer is one of the most common and deadliest cancers in the world, particularly esophageal adenocarcinoma. There has never been a special drug to treat it.Purpose: This article summarizes the work that we have done in our laboratory about the role of CCN1 in esophageal cancer and gives a new perspective of CCN1 biology.Research Design: This is a review article. Study Sample: The work was done using validated cell lines and fixed human tissue slides.Data Collection and Analysis: This is a review article, therefore, no data collection or analysis was involved.Results: CCN1 is a matricellular protein supporting adhesion, migration, and survival in normal cells, but in the esophageal cancer cells, it induces TRAIL-mediated apoptosis. CCN1 promotes TRAIL and its death receptor expression but downregulates the decoy receptors and survivin in a p53-dependant manner. It was thought that CCN1 relies on TNF to induce apoptosis, but our study found that these two molecules antagonize each other. CCN1 promotes TNFR1 cleavage and uses the soluble product to block TNF signaling, while TNF upregulates PGLYRP1 to overcome this obstacle because PGLYRP1 is a secreted protein that competes with TNF for TNFR1 binding. As a result, when CCN1 and TNF are present together in the vicinity of esophageal tumors, they cancel each other out.Conclusions: Based on our laboratory study, CCN1 has much potential to be a candidate for the treatment of esophageal cancer.
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Affiliation(s)
- Zhiheng Chang
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Tong Dang
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Xianmei Meng
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Jianyuan Chai
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China.,Laboratory of Gastrointestinal Injury and Cancer, VA Long Beach Healthcare System, Long Beach, CA, USA.,College of Medicine, University of California, Irvine, CA, USA
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24
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Marwarha G, Røsand Ø, Scrimgeour N, Slagsvold KH, Høydal MA. miR-210 Regulates Apoptotic Cell Death during Cellular Hypoxia and Reoxygenation in a Diametrically Opposite Manner. Biomedicines 2021; 10:42. [PMID: 35052722 PMCID: PMC8772724 DOI: 10.3390/biomedicines10010042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/20/2021] [Accepted: 12/23/2021] [Indexed: 12/20/2022] Open
Abstract
Apoptotic cell death of cardiomyocytes is a characteristic hallmark of ischemia-reperfusion (I/R) injury. The master hypoxamiR, microRNA-210 (miR-210), is considered the primary driver of the cellular response to hypoxic stress. However, to date, no consensus has emerged with regards to the polarity of the miR-210-elicited cellular response, as miR-210 has been shown to exacerbate as well as attenuate hypoxia-driven apoptotic cell death. Herein, in AC-16 cardiomyocytes subjected to hypoxia-reoxygenation (H-R) stress, we unravel novel facets of miR-210 biology and resolve the biological response mediated by miR-210 into the hypoxia and reoxygenation temporal components. Using transient overexpression and decoy/inhibition vectors to modulate miR-210 expression, we elucidated a Janus role miR-210 in the cellular response to H-R stress, wherein miR-210 mitigated the hypoxia-induced apoptotic cell death but exacerbated apoptotic cell death during cellular reoxygenation. We further delineated the underlying cellular mechanisms that confer this diametrically opposite effect of miR-210 on apoptotic cell death. Our exhaustive biochemical assays cogently demonstrate that miR-210 attenuates the hypoxia-driven intrinsic apoptosis pathway, while significantly augmenting the reoxygenation-induced caspase-8-mediated extrinsic apoptosis pathway. Our study is the first to unveil this Janus role of miR-210 and to substantiate the cellular mechanisms that underlie this functional duality.
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Affiliation(s)
- Gurdeep Marwarha
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Technology and Science (NTNU), 7030 Trondheim, Norway; (G.M.); (Ø.R.); (N.S.); (K.H.S.)
| | - Øystein Røsand
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Technology and Science (NTNU), 7030 Trondheim, Norway; (G.M.); (Ø.R.); (N.S.); (K.H.S.)
| | - Nathan Scrimgeour
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Technology and Science (NTNU), 7030 Trondheim, Norway; (G.M.); (Ø.R.); (N.S.); (K.H.S.)
| | - Katrine Hordnes Slagsvold
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Technology and Science (NTNU), 7030 Trondheim, Norway; (G.M.); (Ø.R.); (N.S.); (K.H.S.)
- Department of Cardiothoracic Surgery, St. Olavs University Hospital, 7030 Trondheim, Norway
| | - Morten Andre Høydal
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Technology and Science (NTNU), 7030 Trondheim, Norway; (G.M.); (Ø.R.); (N.S.); (K.H.S.)
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25
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Huang CC, Cheng YC, Lin YC, Chou CH, Ho CT, Wang HK, Way TD. CSC-3436 sensitizes triple negative breast cancer cells to TRAIL-induced apoptosis through ROS-mediated p38/CHOP/death receptor 5 signaling pathways. ENVIRONMENTAL TOXICOLOGY 2021; 36:2578-2588. [PMID: 34599545 DOI: 10.1002/tox.23372] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 06/13/2023]
Abstract
Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) shows little or no toxicity in most normal cells and preferentially induces apoptosis in a variety of malignant cells. However, patients develop resistance to TRAIL, therefore, sensitizing agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are necessary. In this study, we investigated the effect of 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436), an useful flavonoid, to overcome the TRAIL-resistant triple negative breast cancer (TNBC) cells. We found that CSC-3436 potentiated TRAIL-induced apoptosis in TRAIL-resistant TNBC cells and this correlated with the upregulation of death receptors (DR)-5 and down-regulation of decreased decoy receptor (DcR)-1 expression. When examined for its mechanism, we found that the decreased expression of anti-apoptotic proteins c-FLIPS/L, Bcl-Xl, Bcl-2, Survivin, and XIAP. CSC-3436 would increase the expression of Bax and promoted the cleavage of bid. In addition, the induction of DR5 by CSC-3436 was found to be dependent on the modulation of reactive oxygen species (ROS)/p38/C/EBP-homologous protein (CHOP) signaling pathways. Overall, our results indicated that CSC-3436 could potentiate the apoptotic effects of TRAIL through down-regulation of cell survival proteins and upregulation of DR5 via the ROS-mediated upregulation of CHOP protein.
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Affiliation(s)
- Chun-Chen Huang
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan
| | - Yi-Ching Cheng
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan
| | - Ying-Chao Lin
- Division of Neurosurgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
- Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Chun-Hung Chou
- Ph.D. Program for Biotechnology Industry, College of Life Sciences, China Medical University, Taichung, Taiwan
| | - Chi-Tang Ho
- Department of Food Science, Rutgers University, New Brunswick, New Jersey, USA
| | - Hao-Kuang Wang
- Department of Neurosurgery, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
- School of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Tzong-Der Way
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan
- Ph.D. Program for Biotechnology Industry, College of Life Sciences, China Medical University, Taichung, Taiwan
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
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26
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Sadri Nahand J, Rabiei N, Fathazam R, Taghizadieh M, Ebrahimi MS, Mahjoubin-Tehran M, Bannazadeh Baghi H, Khatami A, Abbasi-Kolli M, Mirzaei HR, Rahimian N, Darvish M, Mirzaei H. Oncogenic viruses and chemoresistance: What do we know? Pharmacol Res 2021; 170:105730. [PMID: 34119621 DOI: 10.1016/j.phrs.2021.105730] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/05/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022]
Abstract
Chemoresistance is often referred to as a major leading reason for cancer therapy failure, causing cancer relapse and further metastasis. As a result, an urgent need has been raised to reach a full comprehension of chemoresistance-associated molecular pathways, thereby designing new therapy methods. Many of metastatic tumor masses are found to be related with a viral cause. Although combined therapy is perceived as the model role therapy in such cases, chemoresistant features, which is more common in viral carcinogenesis, often get into way of this kind of therapy, minimizing the chance of survival. Some investigations indicate that the infecting virus dominates other leading factors, i.e., genetic alternations and tumor microenvironment, in development of cancer cell chemoresistance. Herein, we have gathered the available evidence on the mechanisms under which oncogenic viruses cause drug-resistance in chemotherapy.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Saeid Ebrahimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology and Nanotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - AliReza Khatami
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Maryam Darvish
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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27
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Karimi F, Mollaei H. Potential of miRNAs in cervical cancer chemoresistance. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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28
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Köberle B, Schoch S. Platinum Complexes in Colorectal Cancer and Other Solid Tumors. Cancers (Basel) 2021; 13:cancers13092073. [PMID: 33922989 PMCID: PMC8123298 DOI: 10.3390/cancers13092073] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary Cisplatin is successfully used for the treatment of various solid cancers. Unfortunately, it shows no activity in colorectal cancer. The resistance phenotype of colorectal cancer cells is mainly caused by alterations in p53-controlled DNA damage signaling and/or defects in the cellular mismatch repair pathway. Improvement of platinum-based chemotherapy in cisplatin-unresponsive cancers, such as colorectal cancer, might be achieved by newly designed cisplatin analogues, which retain activity in unresponsive tumor cells. Moreover, a combination of cisplatin with biochemical modulators of DNA damage signaling might sensitize cisplatin-resistant tumor cells to the drug, thus providing another strategy to improve cancer therapy. Abstract Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.
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Affiliation(s)
- Beate Köberle
- Department of Food Chemistry and Toxicology, Karlsruhe Institute of Technology, Adenauerring 20a, 76131 Karlsruhe, Germany
| | - Sarah Schoch
- Department of Laboratory Medicine, Lund University, Scheelevägen 2, 223 81 Lund, Sweden
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29
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Chen Y, Liang J, Liang X, Chen J, Wang Y, Cao J, Sun C, Ye J, Chen Q. Limonin induces apoptosis of HL-60 cells by inhibiting NQO1 activity. Food Sci Nutr 2021; 9:1860-1869. [PMID: 33841805 PMCID: PMC8020947 DOI: 10.1002/fsn3.2109] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 12/19/2020] [Accepted: 12/23/2020] [Indexed: 11/10/2022] Open
Abstract
Limonin is an important bioactive substance in citrus fruits, especially in seeds, which has great potential in cancer prevention and treatment. In order to explore the anticancer activity based on interaction between limonin and NQO1, Human promyelocytic leukemia cells (HL-60) were studied in vitro. We found that limonin could inhibit proliferation and promote apoptosis of HL-60 cells, and the effect was positively correlated with its dosage. Western blot results showed that limonin could activate the endogenous apoptosis pathway mediated by mitochondria via up-regulating pro-apoptotic proteins (Bax, cytochrome c, Caspase3, and Caspase9) and down-regulating anti-apoptotic proteins (Bcl-2), thus inhibiting the proliferation of HL-60 cells and promoting apoptosis, which further proved the anticancer activity of limonin from the molecular mechanism. At the same time, limonin down-regulated the expression of NQO1, indicating that limonin may indirectly act on the apoptosis pathway by regulating the expression activity of antioxidant enzymes in vivo, thus exerting its inhibitory effect on tumor cells, which provides an idea for the molecular mechanism that natural products can indirectly exert their anticancer effect by regulating the activity of antioxidant enzymes.
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Affiliation(s)
- Yunyi Chen
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality ImprovementZhejiang UniversityHangzhouChina
| | - Jiaojiao Liang
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality ImprovementZhejiang UniversityHangzhouChina
| | - Xiao Liang
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality ImprovementZhejiang UniversityHangzhouChina
| | - Jiebiao Chen
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality ImprovementZhejiang UniversityHangzhouChina
| | - Yue Wang
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality ImprovementZhejiang UniversityHangzhouChina
| | - Jinping Cao
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality ImprovementZhejiang UniversityHangzhouChina
| | - Chongde Sun
- Laboratory of Fruit Quality Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality ImprovementZhejiang UniversityHangzhouChina
| | - Jiaming Ye
- Zanyu TechnologyQingshan Lake Science and Technology CityHangzhouChina
| | - Qingjun Chen
- Zanyu TechnologyQingshan Lake Science and Technology CityHangzhouChina
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30
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Cytotoxic Efficacy and Resistance Mechanism of a TRAIL and VEGFA-Peptide Fusion Protein in Colorectal Cancer Models. Int J Mol Sci 2021; 22:ijms22063160. [PMID: 33808900 PMCID: PMC8003782 DOI: 10.3390/ijms22063160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 11/16/2022] Open
Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein capable of selectively inducing apoptosis in cancer cells by binding to its cognate receptors. Here, we examined the anticancer efficacy of a recently developed chimeric AD-O51.4 protein, a TRAIL fused to the VEGFA-originating peptide. We tested AD-O51.4 protein activity against human colorectal cancer (CRC) models and investigated the resistance mechanism in the non-responsive CRC models. The quantitative comparison of apoptotic activity between AD-O51.4 and the native TRAIL in nine human colorectal cancer cell lines revealed dose-dependent toxicity in seven of them; the immunofluorescence-captured receptor abundance correlated with the extent of apoptosis. AD-O51.4 reduced the growth of CRC patient-derived xenografts (PDXs) with good efficacy. Cell lines that acquired AD-O51.4 resistance showed a significant decrease in surface TRAIL receptor expression and apoptosis-related proteins, including Caspase-8, HSP60, and p53. These results demonstrate the effectiveness of AD-O51.4 protein in CRC preclinical models and identify the potential mechanism underlying acquired resistance. Progression of AD-O51.4 to clinical trials is expected.
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31
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Ochiiwa H, Ailiken G, Yokoyama M, Yamagata K, Nagano H, Yoshimura C, Muraoka H, Ishida K, Haruma T, Nakayama A, Hashimoto N, Murata K, Nishimura M, Kawashima Y, Ohara O, Ohkubo S, Tanaka T. TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia. Oncogene 2021; 40:1217-1230. [PMID: 33420360 PMCID: PMC7892340 DOI: 10.1038/s41388-020-01586-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 11/07/2020] [Accepted: 11/24/2020] [Indexed: 01/07/2023]
Abstract
TAS4464, a potent, selective small molecule NEDD8-activating enzyme (NAE) inhibitor, leads to inactivation of cullin-RING E3 ubiquitin ligases (CRLs) and consequent accumulations of its substrate proteins. Here, we investigated the antitumor properties and action mechanism of TAS4464 in acute myeloid leukemia (AML). TAS4464 induced apoptotic cell death in various AML cell lines. TAS4464 treatments resulted in the activation of both the caspase-9-mediated intrinsic apoptotic pathway and caspase-8-mediated extrinsic apoptotic pathway in AML cells; combined treatment with inhibitors of these caspases markedly diminished TAS4464-induced apoptosis. In each apoptotic pathway, TAS4464 induced the mRNA transcription of the intrinsic proapoptotic factor NOXA and decreased that of the extrinsic antiapoptotic factor c-FLIP. RNA-sequencing analysis showed that the signaling pathway of the CRL substrate c-Myc was enriched after TAS4464 treatment. Chromatin immunoprecipitation (ChIP) assay revealed that TAS4464-induced c-Myc bound to the PMAIP1 (encoding NOXA) and CFLAR (encoding c-FLIP) promoter regions, and siRNA-mediated c-Myc knockdown neutralized both TAS4464-mediated NOXA induction and c-FLIP downregulation. TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model. These findings suggest that NAE inhibition leads to anti-AML activity via a novel c-Myc-dependent apoptosis induction mechanism.
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Affiliation(s)
- Hiroaki Ochiiwa
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan
| | - Guzhanuer Ailiken
- Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Masataka Yokoyama
- Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Kazuyuki Yamagata
- Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Hidekazu Nagano
- Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Chihoko Yoshimura
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan
| | - Hiromi Muraoka
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan
| | - Keiji Ishida
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan
| | - Tomonori Haruma
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan
| | - Akitoshi Nakayama
- Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Naoko Hashimoto
- Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Kazutaka Murata
- Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan
| | - Motoi Nishimura
- Division of Laboratory Medicine, Clinical Genetics and Proteomics, Chiba University Hospital, Chiba, 260-8670, Japan
| | - Yusuke Kawashima
- Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Chiba, 292-0818, Japan
| | - Osamu Ohara
- Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Chiba, 292-0818, Japan
| | - Shuichi Ohkubo
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan.
| | - Tomoaki Tanaka
- Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.
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Park SY, Kim KY, Jun DY, Hwang SK, Kim YH. G 1 Cell Cycle Arrest and Extrinsic Apoptotic Mechanisms Underlying the Anti-Leukemic Activity of CDK7 Inhibitor BS-181. Cancers (Basel) 2020; 12:cancers12123845. [PMID: 33352782 PMCID: PMC7766600 DOI: 10.3390/cancers12123845] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/11/2020] [Accepted: 12/16/2020] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Chemotherapy resistance in human T-cell acute lymphoblastic leukemia (T-ALL), an aggressive neoplasm, results in poor prognosis despite advances in treatment modalities. Toward the identification of an effective alternative, in the present study, we elucidated the mechanism underlying the antitumor activity of the CDK7 inhibitor BS-181 using malignant cells (Jurkat A3, U937, and HeLa) and normal human peripheral T cells. This is the first report to demonstrate that BS-181 antitumor activity is mainly caused by extrinsic apoptosis induction through cell-surface TRAIL/DR5 levels in human T-ALL Jurkat T cells. Moreover, combined treatment with recombinant TRAIL (rTRAIL) exerted synergistic effects on BS-181 cytotoxicity against malignant cells but not normal human peripheral T cells by augmenting both the extrinsic and intrinsic BCL-2-sensitive apoptosis pathways. Our findings suggest that the combination with rTRAIL may facilitate BS-181 antitumor activity against T-ALL cells while minimizing associated side effects, therefore potentially being applicable to clinical human T-ALL treatment. Abstract In vitro antitumor activity of the CDK7 inhibitor BS-181 against human T-ALL Jurkat cells was determined. Treatment of Jurkat clones (JT/Neo) with BS-181 caused cytotoxicity and several apoptotic events, including TRAIL/DR4/DR5 upregulation, c-FLIP down-regulation, BID cleavage, BAK activation, ΔΨm loss, caspase-8/9/3 activation, and PARP cleavage. However, the BCL-2-overexpressing Jurkat clone (JT/BCL-2) abrogated these apoptotic responses. CDK7 catalyzed the activating phosphorylation of CDK1 (Thr161) and CDK2 (Thr160), and CDK-directed retinoblastoma phosphorylation was attenuated in both BS-181-treated Jurkat clones, whereas only JT/BCL-2 cells exhibited G1 cell cycle arrest. The G1-blocker hydroxyurea augmented BS-181-induced apoptosis by enhancing TRAIL/DR4/DR5 upregulation and c-FLIP down-regulation. BS-181-induced FITC–annexin V-positive apoptotic cells were mostly in the sub-G1 and G1 phases. BS-181-induced cytotoxicity and mitochondrial apoptotic events (BAK activation/ΔΨm loss/caspase-9 activation) in Jurkat clones I2.1 (FADD-deficient) and I9.2 (caspase-8-deficient) were significantly lower than in A3 (wild-type). Exogenously added recombinant TRAIL (rTRAIL) markedly synergized BS-181-induced apoptosis in A3 cells but not in normal peripheral T cells. The cotreatment cytotoxicity was significantly reduced by the DR5-blocking antibody but not by the DR4-blocking antibody. These results demonstrated that the BS-181 anti-leukemic activity is attributed to extrinsic TRAIL/DR5-dependent apoptosis preferentially induced in G1-arrested cells, and that BS-181 and rTRAIL in combination may hold promise for T-ALL treatment.
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Affiliation(s)
- Shin Young Park
- Laboratory of Immunobiology, School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea; (S.Y.P.); (K.Y.K.)
| | - Ki Yun Kim
- Laboratory of Immunobiology, School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea; (S.Y.P.); (K.Y.K.)
| | - Do Youn Jun
- Astrogen Inc., Techno-Building 313, Kyungpook National University, Daegu 41566, Korea; (D.Y.J.); (S.-K.H.)
| | - Su-Kyeong Hwang
- Astrogen Inc., Techno-Building 313, Kyungpook National University, Daegu 41566, Korea; (D.Y.J.); (S.-K.H.)
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu 41566, Korea
| | - Young Ho Kim
- Laboratory of Immunobiology, School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea; (S.Y.P.); (K.Y.K.)
- Correspondence: ; Tel.: +82-53-950-5378; Fax: +82-53-955-5522
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Gene Expression Alterations Associated with Oleuropein-Induced Antiproliferative Effects and S-Phase Cell Cycle Arrest in Triple-Negative Breast Cancer Cells. Nutrients 2020; 12:nu12123755. [PMID: 33297339 PMCID: PMC7762327 DOI: 10.3390/nu12123755] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/18/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023] Open
Abstract
It is known that the Mediterranean diet is effective in reducing the risk of several chronic diseases, including cancer. A critical component of the Mediterranean diet is olive oil, and the relationship between olive oil consumption and the reduced risk of cancer has been established. Oleuropein (OL) is the most prominent polyphenol component of olive fruits and leaves. This compound has been shown to have potent properties in various types of cancers, including breast cancer. In the present study, the molecular mechanism of OL was examined in two racially different triple-negative breast cancer (TNBC) cell lines-African American (AA, MDA-MB-468) and Caucasian American (CA, MDA-MB-231). The data obtained showed that OL effectively inhibits cell growth in both cell lines, concomitant with S-phase cell cycle arrest-mediated apoptosis. The results also showed that OL-treated MDA-MB-468 cells were two-fold more sensitive to OL antiproliferative effect than MDA-MB-231 cells were. At lower concentrations, OL modified the expression of many apoptosis-involved genes. OL was more effective in MDA-MB-468, compared to MDA-MB-231 cells, in terms of the number and the fold-change of the altered genes. In MDA-MB-468 cells, OL induced a noticeable transcription activation in fourteen genes, including two members of the caspase family: caspase 1 (CASP1) and caspase 14 (CASP14); two members of the TNF receptor superfamily: Fas-associated via death domain (FADD) and TNF receptor superfamily 21 (TNFRSF21); six other proapoptotic genes: growth arrest and DNA damage-inducible 45 alpha (GADD45A), cytochrome c somatic (CYCS), BCL-2 interacting protein 2 (BNIP2), BCL-2 interacting protein 3 (BNIP3), BH3 interacting domain death agonist (BID), and B-cell lymphoma/leukemia 10 (BCL10); and the CASP8 and FADD-like apoptosis regulator (CFLAR) gene. Moreover, in MDA-MB-468 cells, OL induced a significant upregulation in two antiapoptotic genes: bifunctional apoptosis regulator (BFAR) and B-Raf proto-oncogene (BRAF) and a baculoviral inhibitor of apoptosis (IAP) repeat-containing 3 (BIRC3). On the contrary, in MDA-MB-231 cells, OL showed mixed impacts on gene expression. OL significantly upregulated the mRNA expression of four genes: BIRC3, receptor-interacting serine/threonine kinase 2 (RIPK2), TNF receptor superfamily 10A (TNFRSF10A), and caspase 4 (CASP4). Additionally, another four genes were repressed, including caspase 6 (CASP6), pyrin domain (PYD), and caspase recruitment domain (CARD)-containing (PAYCARD), baculoviral IAP repeat-containing 5 (BIRC5), and the most downregulated TNF receptor superfamily member 11B (TNFRSF11B, 16.34-fold). In conclusion, the data obtained indicate that the two cell lines were markedly different in the anticancer effect and mechanisms of oleuropein's ability to alter apoptosis-related gene expressions. The results obtained from this study should also guide the potential utilization of oleuropein as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.
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Maiese A, De Matteis A, Bolino G, Turillazzi E, Frati P, Fineschi V. Hypo-Expression of Flice-Inhibitory Protein and Activation of the Caspase-8 Apoptotic Pathways in the Death-Inducing Signaling Complex Due to Ischemia Induced by the Compression of the Asphyxiogenic Tool on the Skin in Hanging Cases. Diagnostics (Basel) 2020; 10:938. [PMID: 33198065 PMCID: PMC7696535 DOI: 10.3390/diagnostics10110938] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/06/2020] [Accepted: 11/10/2020] [Indexed: 11/16/2022] Open
Abstract
The FLICE-inhibitory protein (c-FLIPL) (55 kDa) is expressed in numerous tissues and most abundantly in the kidney, skeletal muscles and heart. The c-FLIPL has a region of homology with caspase-8 at the carboxy-terminal end which allows the molecule to assume a tertiary structure similar to that of caspases-8 and -10. Consequently, c-FLIPL acts as a negative inhibitor of caspase-8, preventing the processing and subsequent release of the pro-apoptotic molecule active form. The c-FLIP plays as an inhibitor of apoptosis induced by a variety of agents, such as tumor necrosis factor (TNF), T cell receptor (TCR), TNF-related apoptosis inducing ligand (TRAIL), Fas and death receptor (DR). Increased expression of c-FLIP has been found in many human malignancies and shown to be involved in resistance to CD95/Fas and TRAIL receptor-induced apoptosis. We wanted to verify an investigative protocol using FLIP to make a differential diagnosis between skin sulcus with vitality or non-vital skin sulcus in hanged subjects and those undergoing simulated hanging (suspension of the victim after murder). The study group consisted of 21 cases who died from suicidal hanging. The control group consisted of traumatic or natural deaths, while a third group consisted of simulated hanging cases. The reactions to the Anti-FLIP Antibody (Abcam clone-8421) was scored for each section with a semi-quantitative method by means of microscopic observation carried out with confocal microscopy and three-dimensional reconstruction. The results obtained allow us to state that the skin reaction to the FLIP is extremely clear and precise, allowing a diagnosis of unequivocal vitality and a very objective differentiation with the post-mortal skin sulcus.
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Affiliation(s)
- Aniello Maiese
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa PI, Italy; (A.M.); (E.T.)
- IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Neuromed Mediterranean Neurological Institute, Via Atinense 18, 86077 Pozzilli IS, Italy;
| | - Alessandra De Matteis
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome RM, Italy; (A.D.M.); (G.B.)
| | - Giorgio Bolino
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome RM, Italy; (A.D.M.); (G.B.)
| | - Emanuela Turillazzi
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa PI, Italy; (A.M.); (E.T.)
| | - Paola Frati
- IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Neuromed Mediterranean Neurological Institute, Via Atinense 18, 86077 Pozzilli IS, Italy;
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome RM, Italy; (A.D.M.); (G.B.)
| | - Vittorio Fineschi
- IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Neuromed Mediterranean Neurological Institute, Via Atinense 18, 86077 Pozzilli IS, Italy;
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome RM, Italy; (A.D.M.); (G.B.)
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Bai ZQ, Liu B, Ma X, Hu K. Backbone and side-chain chemical shift assignments of a cellular FLICE-inhibitory protein (c-FLIP S). BIOMOLECULAR NMR ASSIGNMENTS 2020; 14:239-243. [PMID: 32506385 DOI: 10.1007/s12104-020-09953-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 05/29/2020] [Indexed: 06/11/2023]
Abstract
Cellular FLICE-inhibitory protein (c-FLIP), which is involved in regulating the apoptosis of the extrinsic cell death pathway contains two death effector domains (DED). There are several splicing variants including short-form (c-FLIPS) and long-form (c-FLIPL). The death-inducing signaling complex (DISC) initiates apoptosis and programmed necrosis, DISC assembly and activation are regulated by c-FLIP. Here we report the NMR chemical shift assignments of c-FLIPs, which pave the way for investigating the molecular basis of the anti-apoptotic function of c-FLIPS.
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Affiliation(s)
- Zhi-Qiang Bai
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 132 Lanhei Road, Heilongtan, Kunming, 650201, Yunnan, People's Republic of China
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Bin Liu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 132 Lanhei Road, Heilongtan, Kunming, 650201, Yunnan, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaofang Ma
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Kaifeng Hu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 132 Lanhei Road, Heilongtan, Kunming, 650201, Yunnan, People's Republic of China.
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Gao XZ, Zhang ZX, Han GL. MiR-29a-3p Enhances the Viability of Rat Neuronal Cells that Injured by Oxygen-Glucose Deprivation/Reoxygenation Treatment Through Targeting TNFRSF1A and Regulating NF-κB Signaling Pathway. J Stroke Cerebrovasc Dis 2020; 29:105210. [PMID: 33066952 DOI: 10.1016/j.jstrokecerebrovasdis.2020.105210] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 07/21/2020] [Accepted: 07/25/2020] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE We attempt to investigate the role of TNFRSF1A and its underlying mechanism in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in rat pheochromocytoma PC12 cells. METHODS Public datasets GSE61616 and GSE106680 were downloaded from GEO database. PC12 cells were used to construct OGD/R models. QRT-PCR and western blot were implemented to test the relative mRNA and protein levels, respectively. The miRNA online prediction website TargetScan was used to predict TNFRSF1A upstream regulated miRNAs, which were then confirmed by luciferase reporter assay. The changes in cell viability and apoptosis were evaluated using cell counting kit 8 (CCK-8), lactose dehydrogenase (LDH), and flow cytometry assays. RESULTS Bioinformatics analysis demonstrated that the expression of TNFRSF1A was upregulated in CI/RI and middle cerebral artery occlusion models compared with control, respectively. And a significant upregulation was also observed in OGD/R-damaged PC12 cells. Depletion of TNFRSF1A can notably enhance the cells proliferation after OGD/R treatment, while enlargement of TNFRSF1A presented the opposite outcomes. Moreover, miR-29a-3p was shown to be the upstream regulatory miRNA of TNFRSF1A. The levels of TNFRSF1A were inversely mediated by miR-29a-3p. Overexpression of miR-29a-3p can raise the cell viability, decrease the LDH activity, and reduce the apoptotic ratio in OGD/R-treated cells. Besides, TNFRSF1A can attenuate the protective effect of miR-29a-3p on OGD/R-treated cells. Furthermore, miR-29a-3p mimic inhibited, while overexpression of TNFRSF1A promoted the activation of NF-κB signaling pathway, and TNFRSF1A can attenuate the suppressive effect of miR-29a-3p on the NF-κB pathway. CONCLUSION Our research illustrated that the potential regulatory role of miR-29a-3p/TNFRSF1A axis in neurons cells suffered from OGD/R, and their effects on NF-κB signaling pathway, providing a possible bio-target for protecting cells from OGD/R damage .
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Affiliation(s)
- Xiao-Zeng Gao
- Department of Anesthesiology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China
| | - Zhao-Xia Zhang
- Department of Geriatrics, Shanxian centrol Hospital, Heze, Shandong 274300, P.R. China
| | - Guang-Liang Han
- Department of Neurosurgery, Shengli Oilfield Central Hospital of Binzhou Medical College, Dongying, Shandong 257034, P.R. China.
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Dang T, Chai J. Molecular Dynamics in Esophageal Adenocarcinoma: Who's in Control? Curr Cancer Drug Targets 2020; 20:789-801. [PMID: 32691711 DOI: 10.2174/1568009620666200720011341] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/16/2020] [Accepted: 06/18/2020] [Indexed: 01/01/2023]
Abstract
Esophageal adenocarcinoma (EAC) is one of the fastest-growing cancers in the world. It occurs primarily due to the chronic gastroesophageal reflux disease (GERD), during which the esophageal epithelium is frequently exposed to the acidic fluid coming up from the stomach. This triggers gene mutations in the esophageal cells, which may lead to EAC development. While p53 is activated to get rid of the mutated cells, NFκB orchestrates the remaining cells to heal the wound. However, if the mutations happen to TP53 (a common occasion), the mutant product turns to support tumorigenesis. In this case, NFκB goes along with the mutant p53 to facilitate cancer progression. TRAIL is one of the cytokines produced in response to GERD episodes and it can kill cancer cells selectively, but its clinical use has not been as successful as expected, because some highly sophisticated defense mechanisms against TRAIL have developed during the malignancy. To clear the obstacles for TRAIL action, using a second agent to disarm the cancer cells is required. CCN1 appears to be such a molecule. While supporting normal esophageal cell growth, CCN1 suppresses malignant transformation by inhibiting NFκB and kills the EAC cell through TRAIL-mediated apoptosis.
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Affiliation(s)
- Tong Dang
- Inner Mongolia Institute of Digestive Diseases; Inner Mongolia Engineering Research Center for Prevention and
Treatment of Digestive Diseases; The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 30 Hudemulin Rd, Baotou, 014030, China
| | - Jianyuan Chai
- Inner Mongolia Institute of Digestive Diseases; Inner Mongolia Engineering Research Center for Prevention and
Treatment of Digestive Diseases; The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 30 Hudemulin Rd, Baotou, 014030, China,Laboratory of Gastrointestinal Injury and Cancer, VA Long Beach Healthcare System, Long Beach, CA90822, USA,College of Medicine, University of California, Irvine, CA, 92697, USA
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Zhang S, Shuai L, Wang D, Huang T, Yang S, Miao M, Liu F, Xu J. Pim-1 Protects Retinal Ganglion Cells by Enhancing Their Regenerative Ability Following Optic Nerve Crush. Exp Neurobiol 2020; 29:249-272. [PMID: 32624507 PMCID: PMC7344373 DOI: 10.5607/en20019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/22/2020] [Accepted: 06/22/2020] [Indexed: 11/19/2022] Open
Abstract
Provirus integration site Moloney murine leukemia virus (Pim-1) is a proto-oncogene reported to be associated with cell proliferation, differentiation and survival. This study was to explore the neuroprotective role of Pim-1 in a rat model subjected to optic nerve crush (ONC), and discuss its related molecules in improving the intrinsic regeneration ability of retinal ganglion cells (RGCs). Immunofluorescence staining showed that AAV2- Pim-1 infected 71% RGCs and some amacrine cells in the retina. Real-time PCR and Western blotting showed that retina infection with AAV2- Pim-1 up-regulated the Pim-1 mRNA and protein expressions compared with AAV2-GFP group. Hematoxylin-Eosin (HE) staining, γ-synuclein immunohistochemistry, Cholera toxin B (CTB) tracing and TUNEL showed that RGCs transduction with AAV2-Pim-1 prior to ONC promoted the survival of damaged RGCs and decreased cell apoptosis. RITC anterograde labeling showed that Pim-1 overexpression increased axon regeneration and promoted the recovery of visual function by pupillary light reflex and flash visual evoked potential. Western blotting showed that Pim- 1 overexpression up-regulated the expression of Stat3, p-Stat3, Akt1, p-Akt1, Akt2 and p-Akt2, as well as βIII-tubulin, GAP-43 and 4E-BP1, and downregulated the expression of SOCS1 and SOCS3, Cleaved caspase 3, Bad and Bax. These results demonstrate that Pim-1 exerted a neuroprotective effect by promoting nerve regeneration and functional recovery of RGCs. In addition, it enhanced the intrinsic regeneration capacity of RGCs after ONC by activating Stat3, Akt1 and Akt2 pathways, and inhibiting the mitochondrial apoptosis pathways. These findings suggest that Pim-1 may prove to be a potential therapeutic target for the clinical treatment of optic nerve injury.
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Affiliation(s)
- Shoumei Zhang
- Department of Anatomy, Second Military Medical University, Shanghai 200433, China.,Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Li Shuai
- Department of Health Administration, Second Military Medical University, Shanghai 200433, China
| | - Dong Wang
- Department of Anatomy, Second Military Medical University, Shanghai 200433, China
| | - Tingting Huang
- Department of Anatomy, Second Military Medical University, Shanghai 200433, China
| | - Shengsheng Yang
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai 200433, China
| | - Mingyong Miao
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai 200433, China
| | - Fang Liu
- Department of Anatomy, Second Military Medical University, Shanghai 200433, China
| | - Jiajun Xu
- Department of Anatomy, Second Military Medical University, Shanghai 200433, China
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Huang T, Li H, Zhang S, Liu F, Wang D, Xu J. Nrn1 Overexpression Attenuates Retinal Ganglion Cell Apoptosis, Promotes Axonal Regeneration, and Improves Visual Function Following Optic Nerve Crush in Rats. J Mol Neurosci 2020; 71:66-79. [DOI: 10.1007/s12031-020-01627-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 06/08/2020] [Indexed: 12/20/2022]
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Zhong C, Nong Q, Feng W, Pan Y, Wu Y, Zeng X, Li H, Zhong X, Li F, Luan Z, Huang X, Luo K, Liu D, Yao J. Polyphyllin VII induces fibroblasts apoptosis via the ERK/JNK pathway. Burns 2020; 47:140-149. [PMID: 33279335 DOI: 10.1016/j.burns.2020.03.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 03/02/2020] [Accepted: 03/20/2020] [Indexed: 10/24/2022]
Abstract
Hypertrophic scar (HS) is a pathological scar that often occurs in burn patients. Its histology is characterized by the excessive proliferation of fibroblasts (FB) and excessive accumulation of extracellular matrix (ECM). Inhibition of proliferation and activation of FB is essential for the treatment of HS. The crude extracts of traditional Chinese medicines have beneficial therapeutic effects on HS besides possessing fewer side effects and being easily available. Polyphyllin VII (PP7) is an isoprene saponin isolated from Rhizoma paridis. It has a pro-apoptotic effect on cancer cells. In the present study, we demonstrate that PP7 exerts a significant inhibitory effect on hypertrophic scar fibroblasts (HSFs) in vitro. We also demonstrate that PP7 considerably induces the apoptosis of HSFs and inhibits their activity. Our data show that the PP7-induced HSFs cell apoptosis was mainly due to the enhanced expression of apoptotic genes (Bax, Caspase-3, Caspase-9) and decreased expression of Bcl-2. Moreover, PP7 treatment also enhances the expression of JNK, but that of extracellular protein kinases (ERK) was reduced, and induces apoptosis through ERK/JNK pathways. Thus, PP7 can be used as a drug to prevent the formation of HS.
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Affiliation(s)
- Chaoyi Zhong
- Departments of Burn and Plastic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qingwen Nong
- Departments of Burn and Plastic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Wenyu Feng
- Departments of Orthopedics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yugu Pan
- Departments of Burn and Plastic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yajun Wu
- Departments of Burn and Plastic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xianmin Zeng
- Departments of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Hanwen Li
- Departments of Burn and Plastic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xueran Zhong
- Guangxi Medical University, Nanning, Guangxi, China
| | - Feicui Li
- Departments of General Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhiwei Luan
- Departments of Bone and Joint surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xing Huang
- Departments of Bone and Joint surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Kai Luo
- Guangxi Medical University, Nanning, Guangxi, China
| | - Daen Liu
- Departments of Burn and Plastic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
| | - Jun Yao
- Departments of Bone and Joint surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
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Yuan Z, Yuan Z, Hasnat M, Zhang H, Liang P, Sun L, Jiang Z, Zhang L. A new perspective of triptolide-associated hepatotoxicity: the relevance of NF- κ B and NF- κ B-mediated cellular FLICE-inhibitory protein. Acta Pharm Sin B 2020; 10:861-877. [PMID: 32528833 PMCID: PMC7280150 DOI: 10.1016/j.apsb.2020.02.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/05/2019] [Accepted: 01/02/2020] [Indexed: 02/07/2023] Open
Abstract
Previously, we proposed a new perspective of triptolide (TP)-associated hepatotoxicity: liver hypersensitivity upon lipopolysaccharide (LPS) stimulation. However, the mechanisms for TP/LPS-induced hepatotoxicity remained elusive. The present study aimed to clarify the role of LPS in TP/LPS-induced hepatotoxicity and the mechanism by which TP induces liver hypersensitivity upon LPS stimulation. TNF-α inhibitor, etanercept, was injected intraperitoneally into mice to investigate whether induction of TNF-α by LPS participated in the liver injury induced by TP/LPS co-treatment. Mice and hepatocytes pretreated with TP were stimulated with recombinant TNF-α to assess the function of TNF-α in TP/LPS co-treatment. Additionally, time-dependent NF-κB activation and NF-κB-mediated pro-survival signals were measured in vivo and in vitro. Finally, overexpression of cellular FLICE-inhibitory protein (FLIP), the most potent NF-κB-mediated pro-survival protein, was measured in vivo and in vitro to assess its function in TP/LPS-induced hepatotoxicity. Etanercept counteracted the toxic reactions induced by TP/LPS. TP-treatment sensitized mice and hepatocytes to TNF-α, revealing the role of TNF-α in TP/LPS-induced hepatotoxicity. Mechanistic studies revealed that TP inhibited NF-κB dependent pro-survival signals, especially FLIP, induced by LPS/TNF-α. Moreover, overexpression of FLIP alleviated TP/LPS-induced hepatotoxicity in vivo and TP/TNF-α-induced apoptosis in vitro. Mice and hepatocytes treated with TP were sensitive to TNF-α, which was released from LPS-stimulated immune cells. These and other results show that the TP-induced inhibition of NF-κB-dependent transcriptional activity and FLIP production are responsible for liver hypersensitivity.
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Key Words
- CIAPs, cellular inhibitor of apoptosis proteins
- Etan, etanercept
- FADD, FAS-associated protein with death domain
- FLIP
- FLIP, cellular FLICE-inhibitory protein
- IκB-α, NF-κB inhibitor alpha
- LDH, lactate dehydrogenase
- LPS
- LPS, lipopolysaccharide
- MLKL, mixed lineage kinase domain like pseudokinase
- MPO, myeloperoxidase
- NF-κB
- PAS, periodic acid-schiff
- RIPK1/3, receptor-interacting protein kinase 1/3
- TNF-R1, tumor necrosis factor receptor type 1
- TNF-α
- TNFAIP3, TNF-α-induced protein 3
- TP, triptolide
- TRADD, TNF receptor-associated death domain
- TRAF2, TNF receptor-associated factor 2
- Triptolide
- XIAP, X-linked inhibitor of apoptosis protein
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Affiliation(s)
- Ziqiao Yuan
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Zihang Yuan
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Muhammad Hasnat
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
- Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore 54000, Pakistan
| | - Haoran Zhang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Peishi Liang
- College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Lixin Sun
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Zhenzhou Jiang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 21009, China
| | - Luyong Zhang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
- Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
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Acid/bile exposure triggers TRAIL-mediated apoptosis in esophageal cancer cells by suppressing the decoy receptors and c-FLIP R. Int J Biochem Cell Biol 2020; 122:105736. [PMID: 32135301 DOI: 10.1016/j.biocel.2020.105736] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 02/28/2020] [Accepted: 03/01/2020] [Indexed: 11/23/2022]
Abstract
Esophageal adenocarcinoma essentially develops from esophageal inflammation caused by chronic GERD. During GERD episodes, the lower esophageal epithelium is repeatedly exposed to stomach acid, which often contains duodenal bile salts that prompt malignant transformation. TRAIL is one of the cytokines produced in response to such insults and targets the transformed cells exclusively. In this study, we simulated GERD episodes in vitro by exposing the cancer cells to acid or acid/bile combination and found that the cancer cells lived through acid attacks by expression of the decoy receptors and c-FLIPR but died of TRAIL-mediated apoptosis when bile salts were present. Further investigation revealed that acid/bile exposure downregulated the decoy receptors and thereby facilitated TRAIL signaling; meantime, it inhibited protein kinase C activity and thus expedited c-FLIPR degradation, allowing apoptosis to take place.
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Kim HJ, Seo BG, Kim KD, Yoo J, Lee JH, Min BS, Lee JH, Hwangbo C. C5, A Cassaine Diterpenoid Amine, Induces Apoptosis via the Extrinsic Pathways in Human Lung Cancer Cells and Human Lymphoma Cells. Int J Mol Sci 2020; 21:ijms21041298. [PMID: 32075108 PMCID: PMC7072863 DOI: 10.3390/ijms21041298] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/08/2020] [Accepted: 02/12/2020] [Indexed: 01/12/2023] Open
Abstract
Apoptosis pathways in cells are classified into two pathways: the extrinsic pathway, mediated by binding of the ligand to a death receptor and the intrinsic pathway, mediated by mitochondria. Apoptosis is regulated by various proteins such as Bcl-2 (B-cell lymphoma 2) family and cellular FLICE (Fas-associated Death Domain Protein Interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which have been reported to inhibit caspase-8 activity. In this study, it was found that C5 (3β-Acetyl-nor-erythrophlamide), a compound of cassaine diterpene amine from Erythrophleum fordii, induced cell apoptosis in a variety of types of cancer cells. Induction of apoptosis in cancer cells by C5 was inversely related to the level of Bcl-2 expression. Overexpression of Bcl-2 into cancer cells significantly decreased C5-induced apoptosis. It was also found that treatment of cancer cells with a caspase-8 inhibitor significantly suppressed C5-induced apoptosis; however, treatment with caspase-9 inhibitors did not affect C5-induced apoptosis, suggesting that C5 may induce apoptosis via the extrinsic pathway by activating caspase-8. It was confirmed that treatment with C5 alone induced an association of FADD with procaspase-8; however, overexpression of c-FLIP decreased C5-induced caspase-8 activation. In conclusion, C5 could be utilized as a new useful lead compound for the development of an anti-cancer agent that has the goal of apoptosis.
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Affiliation(s)
- Hyo-Jin Kim
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea; (H.-J.K.); (B.-G.S.); (K.D.K.); (J.Y.)
- Division of Applied Life Science (BK21 Plus), PMBBRC and Research institute of Life Sciences, Geongsang National University, Jinju 52828, Korea
| | - Bo-Gyeong Seo
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea; (H.-J.K.); (B.-G.S.); (K.D.K.); (J.Y.)
- Division of Applied Life Science (BK21 Plus), PMBBRC and Research institute of Life Sciences, Geongsang National University, Jinju 52828, Korea
| | - Kwang Dong Kim
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea; (H.-J.K.); (B.-G.S.); (K.D.K.); (J.Y.)
- Division of Applied Life Science (BK21 Plus), PMBBRC and Research institute of Life Sciences, Geongsang National University, Jinju 52828, Korea
| | - Jiyun Yoo
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea; (H.-J.K.); (B.-G.S.); (K.D.K.); (J.Y.)
- Division of Applied Life Science (BK21 Plus), PMBBRC and Research institute of Life Sciences, Geongsang National University, Jinju 52828, Korea
| | - Joon-Hee Lee
- Department of Animal Bioscience, College of Agriculture and Life Sciences, Gyeongsang National University, Jinju 52828, Korea;
| | - Byung-Sun Min
- College of Pharmacy, Catholic University of Daegu, Daegu 38430, Korea;
| | - Jeong-Hyung Lee
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 24341, Korea
- Correspondence: (J.-H.L.); (C.H.)
| | - Cheol Hwangbo
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea; (H.-J.K.); (B.-G.S.); (K.D.K.); (J.Y.)
- Division of Applied Life Science (BK21 Plus), PMBBRC and Research institute of Life Sciences, Geongsang National University, Jinju 52828, Korea
- Correspondence: (J.-H.L.); (C.H.)
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González-Llorente L, Santacatterina F, García-Aguilar A, Nuevo-Tapioles C, González-García S, Tirpakova Z, Toribio ML, Cuezva JM. Overexpression of Mitochondrial IF1 Prevents Metastatic Disease of Colorectal Cancer by Enhancing Anoikis and Tumor Infiltration of NK Cells. Cancers (Basel) 2019; 12:cancers12010022. [PMID: 31861681 PMCID: PMC7017164 DOI: 10.3390/cancers12010022] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 11/19/2019] [Accepted: 12/13/2019] [Indexed: 02/06/2023] Open
Abstract
Increasing evidences show that the ATPase Inhibitory Factor 1 (IF1), the physiological inhibitor of the ATP synthase, is overexpressed in a large number of carcinomas contributing to metabolic reprogramming and cancer progression. Herein, we show that in contrast to the findings in other carcinomas, the overexpression of IF1 in a cohort of colorectal carcinomas (CRC) predicts less chances of disease recurrence, IF1 being an independent predictor of survival. Bioinformatic and gene expression analyses of the transcriptome of colon cancer cells with differential expression of IF1 indicate that cells overexpressing IF1 display a less aggressive behavior than IF1 silenced (shIF1) cells. Proteomic and functional in vitro migration and invasion assays confirmed the higher tumorigenic potential of shIF1 cells. Moreover, shIF1 cells have increased in vivo metastatic potential. The higher metastatic potential of shIF1 cells relies on increased cFLIP-mediated resistance to undergo anoikis after cell detachment. Furthermore, tumor spheroids of shIF1 cells have an increased ability to escape from immune surveillance by NK cells. Altogether, the results reveal that the overexpression of IF1 acts as a tumor suppressor in CRC with an important anti-metastatic role, thus supporting IF1 as a potential therapeutic target in CRC.
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Affiliation(s)
- Lucía González-Llorente
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Fulvio Santacatterina
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Ana García-Aguilar
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Cristina Nuevo-Tapioles
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Sara González-García
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
| | - Zuzana Tirpakova
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
| | - María Luisa Toribio
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
| | - José M. Cuezva
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain
- Correspondence: ; Tel.: +34-91-196-4618; Fax: +34-91-196-4420
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Zhong HH, Wang HY, Li J, Huang YZ. TRAIL-based gene delivery and therapeutic strategies. Acta Pharmacol Sin 2019; 40:1373-1385. [PMID: 31444476 PMCID: PMC6889127 DOI: 10.1038/s41401-019-0287-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 07/04/2019] [Indexed: 12/11/2022]
Abstract
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), also known as APO2L, belongs to the tumor necrosis factor family. By binding to the death receptor 4 (DR4) or DR5, TRAIL induces apoptosis of tumor cells without causing side toxicity in normal tissues. In recent years TRAIL-based therapy has attracted great attention for its promise of serving as a cancer drug candidate. However, the treatment efficacy of TRAIL protein was under expectation in the clinical trials because of the short half-life and the resistance of cancer cells. TRAIL gene transfection can produce a "bystander effect" of tumor cell killing and provide a potential solution to TRAIL-based cancer therapy. In this review we focus on TRAIL gene therapy and various design strategies of TRAIL DNA delivery including non-viral vectors and cell-based TRAIL therapy. In order to sensitize the tumor cells to TRAIL-induced apoptosis, combination therapy of TRAIL DNA with other drugs by the codelivery methods for yielding a synergistic antitumor efficacy is summarized. The opportunities and challenges of TRAIL-based gene delivery and therapy are discussed.
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Affiliation(s)
- Hui-Hai Zhong
- Shanghai University College of Sciences, Shanghai, 200444, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Hui-Yuan Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jian Li
- Shanghai University College of Sciences, Shanghai, 200444, China
| | - Yong-Zhuo Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
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Li X, Yang Z, Nie W, Jiang J, Li S, Li Z, Tian L, Ma X. Exosomes derived from cardiac progenitor cells attenuate CVB3-induced apoptosis via abrogating the proliferation of CVB3 and modulating the mTOR signaling pathways. Cell Death Dis 2019; 10:691. [PMID: 31534118 PMCID: PMC6751166 DOI: 10.1038/s41419-019-1910-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 08/18/2019] [Accepted: 08/26/2019] [Indexed: 01/01/2023]
Abstract
Viral myocarditis is potentially fatal and lacking a specific treatment. Exosomes secreted by cardiac progenitor cells (CPCs) have emerged as a promising tool for cardioprotection and repair. In this study, we investigated whether CPCs-derived exosomes (CPCs-Ex) could utilize the mTOR signal pathway to reduce the apoptosis in viral myocarditis. In vitro, exosomes were, respectively, added to H9C2 cells after CVB3 infection to detect the anti-apoptosis effect of CPCs-Ex. Compared with the controls, the apoptosis rate was reduced, accompanied with the depressed expression of viral capsid protein 1 (VP1) and pro-apoptosis factors of Bim/caspase families. Meanwhile, the phosphorylation of Akt, mTOR, and p70S6K were promoted, but that of 4EBP1 was suppressed. In vivo, the results of apoptosis, expression of CVB3 and pro-apoptosis factors, and phosphorylation of Akt/mTOR factors of CVB3-infected cardiomyocytes were consistent with that of vitro. Following that, we use Rapamycin and MK-2206 to inhibit the Akt/mTOR signaling pathway, meanwhile, Rattus 4EBP1, p70S6K, Akt1 and Akt2 were transfected to H9C2 cells to establish the stably transfected cell lines. In the group with Rapamycin or MK-2206 pretreatment, CPCs-Ex also could decrease the apoptosis of H9C2 cells and expression of CVB3 mRNA, followed by decreased expression of apoptosis factors. In Akt2, p70S6K and 4EBP1 overexpression groups, CPCs-Ex promoted CVB3-induced apoptosis, VP1 expression and cleavage of caspase-3. Our results therefore identify CPCs-Ex exerts an anti-apoptosis effect in CVB3-infected cells by abrogating the proliferation of CVB3 and modulating the mTOR signaling pathways as well as the expression of Bcl-2 and caspase families. Viral myocarditis, mainly caused by CVB3 infection, is lacking a specific treatment. Our study identified an anti-apoptosis role of CPCs-Ex in CVB3-infected cells and rats, which shown that CPCs-Ex may be an effective tool to treat viral myocarditis. We believe that with more in-depth research on the functionality of CPCs-Ex, there will be a breakthrough in the treatment of viral myocarditis.
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Affiliation(s)
- Xin Li
- Department of Pediatrics, the Third Xiangya Hospital, Central South University, Changsha, China.
| | - Zuocheng Yang
- Department of Pediatrics, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Wenyuan Nie
- Department of Urology, Chinese People's Liberation Army, 89th Hospital, Weifang, Shandong, China
| | - Jie Jiang
- Department of Pediatrics, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Shentang Li
- Department of Pediatrics, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhuoying Li
- Department of Pediatrics, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Lang Tian
- Department of Pediatrics, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Xing Ma
- Sate Key Laboratory of Advanced Welding and Joining, Harbin Institute of Technology (Shenzhen), Shenzhen, China
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Arroyo N, Herlem G, Picaud F. Ligand nanovectorization using graphene to target cellular death receptors of cancer cell. Proteins 2019; 88:94-105. [DOI: 10.1002/prot.25772] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 06/11/2019] [Accepted: 07/06/2019] [Indexed: 02/04/2023]
Affiliation(s)
- Nicolas Arroyo
- Laboratoire de Nanomédecine, Imagerie et Thérapeutique, EA4662, Université Bourgogne‐Franche‐Comté (UFR Sciences et Techniques, UFR Sciences Médicales et Pharmaceutiques), Centre Hospitalier Universitaire de Besançon Besançon France
| | - Guillaume Herlem
- Laboratoire de Nanomédecine, Imagerie et Thérapeutique, EA4662, Université Bourgogne‐Franche‐Comté (UFR Sciences et Techniques, UFR Sciences Médicales et Pharmaceutiques), Centre Hospitalier Universitaire de Besançon Besançon France
| | - Fabien Picaud
- Laboratoire de Nanomédecine, Imagerie et Thérapeutique, EA4662, Université Bourgogne‐Franche‐Comté (UFR Sciences et Techniques, UFR Sciences Médicales et Pharmaceutiques), Centre Hospitalier Universitaire de Besançon Besançon France
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Francois RA, Zhang A, Husain K, Wang C, Hutchinson S, Kongnyuy M, Batra SK, Coppola D, Sebti SM, Malafa MP. Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIP s. Cancer Cell Int 2019; 19:189. [PMID: 31367187 PMCID: PMC6647259 DOI: 10.1186/s12935-019-0876-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 05/28/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Vitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects. METHODS We report a novel function of VEDT in augmenting tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis in pancreatic cancer cells. The effects of VEDT were shown by its ability to trigger caspase-8-dependent apoptosis in pancreatic cancer cells. RESULTS When combined with TRAIL, VEDT significantly augmented TRAIL-induced apoptosis of pancreatic cancer cells. VEDT decreased cellular FLICE inhibitory protein (c-FLIP) levels without consistently modulating the expression of decoy death receptors 1, 2, 3 or death receptors 4 and 5. Enforced expression of c-FLIP substantially attenuated VEDT/TRAIL-induced apoptosis. Thus, c-FLIP reduction plays an important part in mediating VEDT/TRAIL-induced apoptosis. Moreover, VEDT increased c-FLIP ubiquitination and degradation but did not affect its transcription, suggesting that VEDT decreases c-FLIP levels through promoting its degradation. Of note, degradation of c-FLIP and enhanced TRAIL-induced apoptosis in pancreatic cancer cells were observed only with the anticancer bioactive vitamin E compounds δ-, γ-, and β-tocotrienol but not with the anticancer inactive vitamin E compounds α-tocotrienol and α-, β-, γ-, and δ-tocopherol. CONCLUSIONS c-FLIP degradation is a key event for death receptor-induced apoptosis by anticancer bioactive vitamin E compounds in pancreatic cancer cells. Moreover, VEDT augmented TRAIL inhibition of pancreatic tumor growth and induction of apoptosis in vivo. Combination therapy with TRAIL agonists and bioactive vitamin E compounds may offer a novel strategy for pancreatic cancer intervention.
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Affiliation(s)
- Rony A. Francois
- Gastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 USA
| | - Anying Zhang
- Gastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 USA
- Department of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Kazim Husain
- Gastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 USA
| | - Chen Wang
- Gastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 USA
- Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Sean Hutchinson
- Gastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 USA
| | - Michael Kongnyuy
- Gastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 USA
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NB USA
| | - Domenico Coppola
- Department of Anatomical Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL USA
| | - Said M. Sebti
- Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL USA
| | - Mokenge P. Malafa
- Gastrointestinal Oncology Program, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 USA
- Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL USA
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Yan L, Majerciak V, Zheng ZM, Lan K. Towards Better Understanding of KSHV Life Cycle: from Transcription and Posttranscriptional Regulations to Pathogenesis. Virol Sin 2019; 34:135-161. [PMID: 31025296 PMCID: PMC6513836 DOI: 10.1007/s12250-019-00114-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 03/14/2019] [Indexed: 02/08/2023] Open
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), is etiologically linked to the development of Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. These malignancies often occur in immunosuppressed individuals, making KSHV infection-associated diseases an increasing global health concern with persistence of the AIDS epidemic. KSHV exhibits biphasic life cycles between latent and lytic infection and extensive transcriptional and posttranscriptional regulation of gene expression. As a member of the herpesvirus family, KSHV has evolved many strategies to evade the host immune response, which help the virus establish a successful lifelong infection. In this review, we summarize the current research status on the biology of latent and lytic viral infection, the regulation of viral life cycles and the related pathogenesis.
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Affiliation(s)
- Lijun Yan
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Vladimir Majerciak
- National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA
| | - Zhi-Ming Zheng
- National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
| | - Ke Lan
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
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Díaz-Rodríguez E, Pérez-Peña J, Ríos-Luci C, Arribas J, Ocaña A, Pandiella A. TRAIL receptor activation overcomes resistance to trastuzumab in HER2 positive breast cancer cells. Cancer Lett 2019; 453:34-44. [PMID: 30928382 DOI: 10.1016/j.canlet.2019.03.042] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/20/2019] [Accepted: 03/22/2019] [Indexed: 12/22/2022]
Abstract
The appearance of resistance to the anti-HER2 targeted drug trastuzumab constitutes, nowadays, an important challenge in the oncology clinic. To fight such resistance, we searched for potential vulnerabilities in cells resistant to that drug. To that end, we used cell lines primary resistant to trastuzumab, as well as cells made secondarily resistant to the drug upon continuous exposure. Using genomic and proteomic approaches, a deregulation in cell death pathways was identified in trastuzumab-resistant cells. More precisely, an increased response to the death factor TRAIL, caused by an increase in the cellular receptors for this factor, was observed. In parallel, a decrease in inhibitory components of the pathway was detected. This combination produces a more efficient assembly of the functional complex in the trastuzumab-resistant cells that translates in the observed increased response to TRAIL. Analysis of HER2 positive patient samples confirmed deregulation of this pathway in trastuzumab-resistant patients. Taken together our data identify a vulnerability of trastuzumab-resistant cells that could be used to design new targeted therapies in that context.
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Affiliation(s)
- Elena Díaz-Rodríguez
- Instituto de Biología Molecular y Celular del Cáncer. CSIC-IBSAL, Salamanca, Spain; CIBERONC, Spain.
| | - Javier Pérez-Peña
- Instituto de Biología Molecular y Celular del Cáncer. CSIC-IBSAL, Salamanca, Spain; Translational Research Unit, Albacete University Hospital and Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla la Mancha, Albacete, Spain, and; CIBERONC, Spain
| | - Carla Ríos-Luci
- Instituto de Biología Molecular y Celular del Cáncer. CSIC-IBSAL, Salamanca, Spain; CIBERONC, Spain
| | - Joaquín Arribas
- Vall d´Hebron Institute of Oncology, Barcelona, Spain; CIBERONC, Spain
| | - Alberto Ocaña
- Translational Research Unit, Albacete University Hospital and Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla la Mancha, Albacete, Spain, and; CIBERONC, Spain
| | - Atanasio Pandiella
- Instituto de Biología Molecular y Celular del Cáncer. CSIC-IBSAL, Salamanca, Spain; CIBERONC, Spain.
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