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Li J, Ji H, Xu Y, Zhang W, Yin Y, Zhao Y, Du Y, He A, Zhao D. TUT7-Mediated Uridine Degradation of MCPIP1 in the Pterygium to Regulate TRAF6-Mediated Autophagy. Invest Ophthalmol Vis Sci 2025; 66:41. [PMID: 40238115 PMCID: PMC12011128 DOI: 10.1167/iovs.66.4.41] [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: 09/10/2024] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Purpose Pterygium is a prevalent ocular disorder characterized by the proliferation of fibrovascular tissue beneath the conjunctiva. The precise role of monocyte chemotactic protein-induced protein 1 (MCPIP1) in the pterygium remains elusive. Methods Immunohistochemistry, Western blot, and quantitative RT-PCR were used to analyze the expression of MCPIP1 and other regulators. The role of MCPIP1 in pterygium fibrosis was assessed both in vitro and in vivo. Further, Co-immunoprecipitation and ubiquitination assays were performed to investigate the impact of MCPIP1 on the TRAF6-BECN1 signaling pathway. The role of MCPIP1 in autophagy regulation was studied through immunofluorescence experiments, while transwell migration and wound-healing assays were employed to assess the migratory and proliferative capabilities of human pterygium fibroblast (HPF) cells. Additionally, in vitro transcription and uridylylation experiments provided mechanistic insights into the regulatory role of terminal uridyltransferase 7 (TUT7) on MCPIP1 mRNA. Results The results showed that MCPIP1 negatively regulates the fibrosis and autophagy of HPF cells, thereby inhibiting the development of pterygium. In terms of its mechanism, MCPIP1 facilitated the assembly of the TRAF6-BECN1 complex, augmented BECN1 ubiquitination, induced autophagy, and attenuated cell migration and proliferation abilities while suppressing HPFs' cell fibrosis. The function of MCPIP1 was weakened by TUT7, which reduced the stability of MCPIP1 mRNA and thus alleviated the negative regulatory effect of MCPIP1 on pterygium. Conclusions In summary, the current study revealed that MCPIP1 promotes autophagy by positively regulating the TRAF6-BECN1 signaling pathway, thereby suppressing pterygium development. Conversely, TUT7 uridylylation modulated MCPIP1's regulation of pterygium.
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Affiliation(s)
- Juanjuan Li
- Department of Ophthalmology, Yan'An Hospital of Kunming City, Kunming, Yunnan, China
| | - Hao Ji
- Department of Information, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yanze Xu
- Department of Ophthalmology, Yan'An Hospital of Kunming City, Kunming, Yunnan, China
| | - Weijia Zhang
- Department of Ophthalmology, Yan'An Hospital of Kunming City, Kunming, Yunnan, China
| | - Yuru Yin
- Department of Ophthalmology, Yan'An Hospital of Kunming City, Kunming, Yunnan, China
| | - Yubing Zhao
- Department of Ophthalmology, Yan'An Hospital of Kunming City, Kunming, Yunnan, China
| | - Yan Du
- Department of Ophthalmology, Yan'An Hospital of Kunming City, Kunming, Yunnan, China
| | - Anni He
- Department of Ophthalmology, Yan'An Hospital of Kunming City, Kunming, Yunnan, China
| | - Dandan Zhao
- Department of Ophthalmology, Yan'An Hospital of Kunming City, Kunming, Yunnan, China
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Levi-D'Ancona E, Walker EM, Zhu J, Deng Y, Sidarala V, Stendahl AM, Reck EC, Henry-Kanarek BA, Lietzke AC, Pasmooij MB, Hubers DL, Basrur V, Ghosh S, Stiles L, Nesvizhskii AI, Shirihai OS, Soleimanpour SA. TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.31.635900. [PMID: 39974969 PMCID: PMC11838480 DOI: 10.1101/2025.01.31.635900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Activation of innate immune signaling occurs during the progression of immunometabolic diseases, including type 2 diabetes (T2D), yet the impact of innate immune signaling on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for glucose homeostasis and pancreatic β-cell function under basal conditions, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and increases in mitophagy following metabolic stress in both mouse and human islets. Indeed, TRAF6 was critical for the recruitment and function of machinery within both the ubiquitin-mediated (Parkin-dependent) and receptor-mediated (Parkin-independent) mitophagy pathways upon metabolic stress. Intriguingly, the effect of TRAF6 deficiency on glucose homeostasis and mitophagy was fully reversed by concomitant Parkin deficiency. Thus, our results implicate a role for TRAF6 in the cross-regulation of both ubiquitin- and receptor- mediated mitophagy through the restriction of Parkin. Together, we illustrate that β-cells engage innate immune signaling to adaptively respond to a diabetogenic environment.
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Alahwany AM, Arisha AH, Abdelkhalek A, Khamis T, Miyasho T, Kirat D. Impact of Ultraviolet C Radiation on Male Fertility in Rats: Suppression of Autophagy, Stimulation of Gonadotropin-Inhibiting Hormone, and Alteration of miRNAs. Int J Mol Sci 2025; 26:316. [PMID: 39796171 PMCID: PMC11720531 DOI: 10.3390/ijms26010316] [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: 11/24/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
While ultraviolet C (UVC) radiation has beneficial applications, it can also pose risks to living organisms. Nevertheless, a detailed assessment of UVC radiation's effects on mammalian male reproductive physiology, including the underlying mechanisms and potential protective strategies, has not yet been accomplished. This study aimed to examine the critical roles of oxidative stress, autophagy, reproductive hormonal axis, and microRNAs in UVC-induced reproductive challenges in male rats. Semen, biochemical, molecular, and in silico analyses revealed significant dysregulation of testicular steroidogenesis, impaired spermatogenesis, deteriorated sperm quality, and altered reproductive hormonal profiles, which ultimately lead to a decline in fertility in male rats exposed to UVC radiation. Our data indicated that the suppression of autophagy, stimulation of gonadotropin-inhibiting hormone (GnIH), and alteration of microRNAs serve as key mediators of UVC-induced stress effects in mammalian reproduction, potentially contributing to male infertility. Targeting these pathways, particularly through pretreatment with hesperidin (HES), offers a promising strategy to counteract UVC-induced male infertility. In conclusion, the present findings emphasize the importance of understanding the molecular mechanisms behind UVC-induced male infertility and offer valuable insights into the protective mechanisms and prospective role of HES in safeguarding male reproductive health.
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Affiliation(s)
- Ahmed Mohamed Alahwany
- Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo (BUC), Badr City 11829, Egypt; (A.M.A.); (A.H.A.)
| | - Ahmed Hamed Arisha
- Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo (BUC), Badr City 11829, Egypt; (A.M.A.); (A.H.A.)
- Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Adel Abdelkhalek
- Faculty of Veterinary Medicine, Badr University in Cairo (BUC), Badr City 11829, Egypt;
| | - Tarek Khamis
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt;
| | - Taku Miyasho
- Laboratory of Animal Biological Responses, Department of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Japan
| | - Doaa Kirat
- Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
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Pallathadka H, Hsu CY, Obaid Saleh R, Renuka Jyothi S, Kumar A, Yumashev A, Sinha A, Hussein Zwamel A, Abed Jawad M, Alsaadi SB. Specific small interfering RNAs (siRNAs) for targeting the metastasis, immune responses, and drug resistance of colorectal cancer cells (CRC). Int Immunopharmacol 2024; 140:112730. [PMID: 39083927 DOI: 10.1016/j.intimp.2024.112730] [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: 06/06/2024] [Revised: 07/05/2024] [Accepted: 07/17/2024] [Indexed: 08/02/2024]
Abstract
Colorectal cancer (CRC) involves various genetic alterations, with liver metastasis posing a significant clinical challenge. Furthermore, CRC cells mostly show an increase in resistance to traditional treatments like chemotherapy. It is essential to investigate more advanced and effective therapies to prevent medication resistance and metastases and extend patient life. As a result, it is anticipated that small interfering RNAs (siRNAs) would be exceptional instruments that can control gene expression by RNA interference (RNAi). In eukaryotes, RNAi is a biological mechanism that destroys specific messenger RNA (mRNA) molecules, thereby inhibiting gene expression. In the management of CRC, this method of treatment represents a potential therapeutic agent. However, it is important to acknowledge that siRNA therapies have significant issues, such as low serum stability and nonspecific absorption into biological systems. Delivery mechanisms are thus being created to address these issues. In the current work, we address the potential benefits of siRNA therapy and outline the difficulties in treating CRCby focusing on the primary signaling pathways linked to metastasis as well as genes implicated in the multi-drug resistance (MDR) process.
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Affiliation(s)
| | - Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, Arizona 85004, USA.
| | - Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq.
| | - S Renuka Jyothi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India.
| | - Ashwani Kumar
- Department of Pharmacy, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Alexey Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Russia.
| | - Aashna Sinha
- School of Applied and Life Sciences, Divison of Research and Innovation Uttaranchal University, Dehradun, Uttarakhand, India
| | - Ahmed Hussein Zwamel
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq; Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical Laboratory Technique college, the Islamic University of Babylon, Babylon, Iraq.
| | | | - Salim B Alsaadi
- Department of Pharmaceutics, Al-Hadi University College, Baghdad 10011, Iraq.
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Walweel N, Aydin O. Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies. ACS OMEGA 2024; 9:27832-27852. [PMID: 38973850 PMCID: PMC11223161 DOI: 10.1021/acsomega.4c02234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/01/2024] [Accepted: 05/30/2024] [Indexed: 07/09/2024]
Abstract
The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.
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Affiliation(s)
- Nada Walweel
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
| | - Omer Aydin
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
- ERNAM-Nanotechnology
Research and Application Center, Erciyes
University, Kayseri 38039, Turkey
- ERKAM-Clinical-Engineering
Research and Implementation Center, Erciyes
University, Kayseri 38030, Turkey
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Ma Q, Yu J, Liu L, Ma X, Zhang J, Zhang J, Wang X, Deng G, Wu X. TRAF6 triggers Mycobacterium-infected host autophagy through Rab7 ubiquitination. Cell Death Discov 2023; 9:427. [PMID: 38016969 PMCID: PMC10684575 DOI: 10.1038/s41420-023-01731-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 11/06/2023] [Accepted: 11/16/2023] [Indexed: 11/30/2023] Open
Abstract
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase that is extensively involved in the autophagy process by interacting with diverse autophagy initiation and autophagosome maturation molecules. However, whether TRAF6 interacts with lysosomal proteins to regulate Mycobacterium-induced autophagy has not been completely characterized. Herein, the present study showed that TRAF6 interacted with lysosomal key proteins Rab7 through RING domain which caused Rab7 ubiquitination and subsequently ubiquitinated Rab7 binds to STX17 (syntaxin 17, a SNARE protein that is essential for mature autophagosome), and thus promoted the fusion of autophagosomes and lysosomes. Furthermore, TRAF6 enhanced the initiation and formation of autophagosomes in Mycobacterium-induced autophagy in both BMDMs and RAW264.7 cells, as evidenced by autophagic flux, colocalization of LC3 and BCG, autophagy rates, and autophagy-associated protein expression. Noteworthy to mention, TRAF6 deficiency exacerbated lung injury and promoted BCG survival. Taken together, these results identify novel molecular and cellular mechanisms by which TRAF6 positively regulates Mycobacterium-induced autophagy.
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Affiliation(s)
- Qinmei Ma
- School of Life Science, Ningxia University, Yinchuan, NingXia, 750021, China
- Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan, NingXia, 750021, China
| | - Jialin Yu
- School of Life Science, Ningxia University, Yinchuan, NingXia, 750021, China
- Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan, NingXia, 750021, China
| | - Li Liu
- School of Life Science, Ningxia University, Yinchuan, NingXia, 750021, China
- Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan, NingXia, 750021, China
| | - Xiaoyan Ma
- School of Life Science, Ningxia University, Yinchuan, NingXia, 750021, China
- Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan, NingXia, 750021, China
| | - Jiaxue Zhang
- School of Life Science, Ningxia University, Yinchuan, NingXia, 750021, China
- Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan, NingXia, 750021, China
| | - Jiamei Zhang
- School of Life Science, Ningxia University, Yinchuan, NingXia, 750021, China
- Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan, NingXia, 750021, China
| | - Xiaoping Wang
- The Fourth People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, NingXia, 750021, China
| | - Guangcun Deng
- School of Life Science, Ningxia University, Yinchuan, NingXia, 750021, China.
- Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan, NingXia, 750021, China.
| | - Xiaoling Wu
- School of Life Science, Ningxia University, Yinchuan, NingXia, 750021, China.
- Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan, NingXia, 750021, China.
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Wang W, Yang Y, Shi Y, Xiang T, Xie J. E3 ubiquitin ligase STUB1 affects the mTORC1 pathway through p62 and participates in regulating the differentiation of follicular helper T cells in rheumatoid arthritis. Clin Immunol 2023; 255:109736. [PMID: 37604355 DOI: 10.1016/j.clim.2023.109736] [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: 06/12/2023] [Revised: 08/04/2023] [Accepted: 08/11/2023] [Indexed: 08/23/2023]
Abstract
OBJECTIVE The abnormal expansion of Tfh cells plays a key role in chronic inflammation of RA joint. We speculated that STUB1 is an important regulatory factor in promoting the differentiation of Tfh cells in RA. CONTENT AND METHODS The proportion of Tfh cells and the level of STUB1 in Tfh cells was measured. CD4+T cells were isolated from PBMCs of RA patients, and the percentage of Tfh cells was detected after up- or down-regulating the expression of STUB1. The levels of mTORC1 pathway activator p-mTOR and p-S6K were measured by Western blot. The ubiquitination of p62 by STUB1 and its ubiquitination type as well as the activation of mTORC1 was detected in vitro, and the activation of the mTORC1 and the differentiation of Tfh cells was detected in STUB1-upregulated CD4+ T cells with overexpressed p62. RESULTS The level of STUB1 is elevated in Tfh cells of patients. Up-regulation of STUB1 can promote the differentiation of Tfh cells. STUB1 promotes the degradation of p62 via K48-linked ubiquitination and promotes the activation of mTORC1. Overexpression of p62 can reverse the promoting effect of STUB1 on the differentiation of Tfh cells and the activation of mTORC1. CONCLUSION STUB1 can promote the differentiation of Tfh cells in RA by mediating the activation of mTORC1 pathway through ubiquitination of p62.
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Affiliation(s)
- Wen Wang
- Department of Rheumatology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yachen Yang
- Department of Rheumatology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yujia Shi
- Department of Rheumatology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ting Xiang
- Department of Rheumatology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jianmin Xie
- Department of Rheumatology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Zeng XY, Qiu XZ, Wu JN, Liang SM, Huang JA, Liu SQ. Interaction mechanisms between autophagy and ferroptosis: Potential role in colorectal cancer. World J Gastrointest Oncol 2023; 15:1135-1148. [PMID: 37546557 PMCID: PMC10401467 DOI: 10.4251/wjgo.v15.i7.1135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/28/2023] [Accepted: 04/23/2023] [Indexed: 07/12/2023] Open
Abstract
Colorectal cancer (CRC) is a common malignancy that has the second highest incidence and mortality rate. Although there are many personalized treatment options for CRC, the therapeutic effects are ultimately limited by drug resistance. Studies have aimed to block the initiation and progression of CRC by inducing cell death to overcome this obstacle. Substantial evidence has indicated that both autophagy and ferroptosis play important regulatory roles in CRC. Autophagy, a lysosome-dependent process by which cellular proteins and organelles are degraded, is the basic mechanism for maintaining cell homeostasis. The duality and complexity of autophagy in cancer therapy is a hot topic of discussion. Ferroptosis, a regulated cell death pathway, is associated with iron accumulation-induced lipid peroxidation. The activation of ferroptosis can suppress CRC proliferation, invasion and drug resistance. Furthermore, recent studies have suggested an interaction between autophagy and ferroptosis. Autophagy can selectively degrade certain cellular contents to provide raw materials for ferroptosis, ultimately achieving antitumor and anti-drug resistance. Therefore, exploring the interaction between autophagy and ferroptosis could reveal novel ideas for the treatment of CRC. In this review, we describe the mechanisms of autophagy and ferroptosis, focusing on their roles in CRC and the crosstalk between them.
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Affiliation(s)
- Xin-Ya Zeng
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Xin-Ze Qiu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Jiang-Ni Wu
- Department of Pathology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Sheng-Mei Liang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Jie-An Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Shi-Quan Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
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Kim JY, Shin JH, Kim MJ, Kang Y, Lee JS, Son J, Jeong SK, Kim D, Kim DH, Chun E, Lee KY. β-arrestin 2 negatively regulates lung cancer progression by inhibiting the TRAF6 signaling axis for NF-κB activation and autophagy induced by TLR3 and TLR4. Cell Death Dis 2023; 14:422. [PMID: 37443143 PMCID: PMC10344878 DOI: 10.1038/s41419-023-05945-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 06/20/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023]
Abstract
β-arrestin 2 (ARRB2) is functionally implicated in cancer progression via various signaling pathways. However, its role in lung cancer remains unclear. To obtain clinical insight on its function in lung cancer, microarray data from lung tumor tissues (LTTs) and matched lung normal tissues (mLNTs) of primary non-small cell lung cancer (NSCLC) patients (n = 37) were utilized. ARRB2 expression levels were markedly decreased in all 37 LTTs compared to those in matched LNTs of NSCLC patients. They were significantly co-related to enrichment gene sets associated with oncogenic and cancer genes. Importantly, Gene Set Enrichment Analysis (GSEA) between three LTTs with highly down-regulated ARRB2 and three LTTs with lowly down-regulated ARRB2 revealed significant enrichments related to toll-like receptor (TLR) signaling and autophagy genes in three LTTs with highly down-regulated ARRB2, suggesting that ARRB2 was negatively involved in TLR-mediated signals for autophagy induction in lung cancer. Biochemical studies for elucidating the molecular mechanism revealed that ARRB2 interacted with TNF receptor-associated factor 6 (TRAF6) and Beclin 1 (BECN1), thereby inhibiting the ubiquitination of TRAF6-TAB2 to activate NF-κB and TRAF6-BECN1 for autophagy stimulated by TLR3 and TLR4, suggesting that ARRB2 could inhibit the TRAF6-TAB2 signaling axis for NF-κB activation and TRAF6-BECN1 signaling axis for autophagy in response to TLR3 and TLR4. Notably, ARRB2-knockout (ARRB2KO) lung cancer cells exhibited marked enhancements of cancer migration, invasion, colony formation, and proliferation in response to TLR3 and TLR4 stimulation. Altogether, our current data suggest that ARRB2 can negatively regulate lung cancer progression by inhibiting TLR3- and TLR4-induced autophagy.
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Affiliation(s)
- Ji Young Kim
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Ji Hye Shin
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Mi-Jeong Kim
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Yeeun Kang
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Ji Su Lee
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Juhee Son
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Soo-Kyung Jeong
- R&D Center, CHA Vaccine Institute, Seongnam-si, 13493, Republic of Korea
| | - Daesik Kim
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Duk-Hwan Kim
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Eunyoung Chun
- R&D Center, CHA Vaccine Institute, Seongnam-si, 13493, Republic of Korea.
| | - Ki-Young Lee
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Samsung Medical Center, Sungkyunkwan University, Seoul, 06351, Republic of Korea.
- Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
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Kim MJ, Kim JY, Shin JH, Kang Y, Lee JS, Son J, Jeong SK, Kim D, Kim DH, Chun E, Lee KY. FFAR2 antagonizes TLR2- and TLR3-induced lung cancer progression via the inhibition of AMPK-TAK1 signaling axis for the activation of NF-κB. Cell Biosci 2023; 13:102. [PMID: 37287005 DOI: 10.1186/s13578-023-01038-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/02/2023] [Indexed: 06/09/2023] Open
Abstract
BACKGROUND Free fatty acid receptors (FFARs) and toll-like receptors (TLRs) recognize microbial metabolites and conserved microbial products, respectively, and are functionally implicated in inflammation and cancer. However, whether the crosstalk between FFARs and TLRs affects lung cancer progression has never been addressed. METHODS We analyzed the association between FFARs and TLRs using The Cancer Genome Atlas (TCGA) lung cancer data and our cohort of non-small cell lung cancer (NSCLC) patient data (n = 42), and gene set enrichment analysis (GSEA) was performed. For the functional analysis, we generated FFAR2-knockout (FFAR2KO) A549 and FFAR2KO H1299 human lung cancer cells and performed biochemical mechanistic studies and cancer progression assays, including migration, invasion, and colony-formation assays, in response to TLR stimulation. RESULTS The clinical TCGA data showed a significant down-regulation of FFAR2, but not FFAR1, FFAR3, and FFAR4, in lung cancer, and a negative correlation with TLR2 and TLR3. Notably, GSEA showed significant enrichment in gene sets related to the cancer module, the innate signaling pathway, and the cytokine-chemokine signaling pathway in FFAR2DownTLR2UpTLR3Up lung tumor tissues (LTTs) vs. FFAR2upTLR2DownTLR3Down LTTs. Functionally, treatment with propionate (an agonist of FFAR2) significantly inhibited human A549 or H1299 lung cancer migration, invasion, and colony formation induced by TLR2 or TLR3 through the attenuation of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB. Moreover, FFAR2KO A549 and FFAR2KO H1299 human lung cancer cells showed marked increases in cell migration, invasion, and colony formation in response to TLR2 or TLR3 stimulation, accompanied by elevations in NF-κB activation, cAMP levels, and the production of C-C motif chemokine ligand (CCL)2, interleukin (IL)-6, and matrix metalloproteinase (MMP) 2 cytokines. CONCLUSION Our results suggest that FFAR2 signaling antagonized TLR2- and TLR3-induced lung cancer progression via the suppression of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB, and its agonist might be a potential therapeutic agent for the treatment of lung cancer.
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Affiliation(s)
- Mi-Jeong Kim
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Ji Young Kim
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Ji Hye Shin
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Yeeun Kang
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Ji Su Lee
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Juhee Son
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Soo-Kyung Jeong
- R&D Center, CHA Vaccine Institute, Seongnam-si, 13493, Republic of Korea
| | - Daesik Kim
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Duk-Hwan Kim
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Eunyoung Chun
- R&D Center, CHA Vaccine Institute, Seongnam-si, 13493, Republic of Korea.
| | - Ki-Young Lee
- Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Samsung Medical Center, Sungkyunkwan University, Seoul, 06351, Republic of Korea.
- Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
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11
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Mao B, Yuan W, Wu F, Yan Y, Wang B. Autophagy in hepatic ischemia-reperfusion injury. Cell Death Discov 2023; 9:115. [PMID: 37019879 PMCID: PMC10076300 DOI: 10.1038/s41420-023-01387-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/23/2023] [Accepted: 02/27/2023] [Indexed: 04/07/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a major complication of liver resection or liver transplantation that can seriously affect patient's prognosis. There is currently no definitive and effective treatment strategy for HIRI. Autophagy is an intracellular self-digestion pathway initiated to remove damaged organelles and proteins, which maintains cell survival, differentiation, and homeostasis. Recent studies have shown that autophagy is involved in the regulation of HIRI. Numerous drugs and treatments can change the outcome of HIRI by controlling the pathways of autophagy. This review mainly discusses the occurrence and development of autophagy, the selection of experimental models for HIRI, and the specific regulatory pathways of autophagy in HIRI. Autophagy has considerable potential in the treatment of HIRI.
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Affiliation(s)
- Benliang Mao
- College of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Wei Yuan
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China
| | - Fan Wu
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China
| | - Yong Yan
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China
| | - Bailin Wang
- College of Clinical Medicine, Guizhou Medical University, Guiyang, China.
- Department of General Surgery, Guangzhou Red Cross Hospital affiliated to Jinan University, Guangzhou, China.
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12
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Shu F, Xiao H, Li QN, Ren XS, Liu ZG, Hu BW, Wang HS, Wang H, Jiang GM. Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets. Signal Transduct Target Ther 2023; 8:32. [PMID: 36646695 PMCID: PMC9842768 DOI: 10.1038/s41392-022-01300-8] [Citation(s) in RCA: 74] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 11/19/2022] [Accepted: 12/18/2022] [Indexed: 01/17/2023] Open
Abstract
Autophagy is a conserved lysosomal degradation pathway where cellular components are dynamically degraded and re-processed to maintain physical homeostasis. However, the physiological effect of autophagy appears to be multifaced. On the one hand, autophagy functions as a cytoprotective mechanism, protecting against multiple diseases, especially tumor, cardiovascular disorders, and neurodegenerative and infectious disease. Conversely, autophagy may also play a detrimental role via pro-survival effects on cancer cells or cell-killing effects on normal body cells. During disorder onset and progression, the expression levels of autophagy-related regulators and proteins encoded by autophagy-related genes (ATGs) are abnormally regulated, giving rise to imbalanced autophagy flux. However, the detailed mechanisms and molecular events of this process are quite complex. Epigenetic, including DNA methylation, histone modifications and miRNAs, and post-translational modifications, including ubiquitination, phosphorylation and acetylation, precisely manipulate gene expression and protein function, and are strongly correlated with the occurrence and development of multiple diseases. There is substantial evidence that autophagy-relevant regulators and machineries are subjected to epigenetic and post-translational modulation, resulting in alterations in autophagy levels, which subsequently induces disease or affects the therapeutic effectiveness to agents. In this review, we focus on the regulatory mechanisms mediated by epigenetic and post-translational modifications in disease-related autophagy to unveil potential therapeutic targets. In addition, the effect of autophagy on the therapeutic effectiveness of epigenetic drugs or drugs targeting post-translational modification have also been discussed, providing insights into the combination with autophagy activators or inhibitors in the treatment of clinical diseases.
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Affiliation(s)
- Feng Shu
- grid.452859.70000 0004 6006 3273Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong China
| | - Han Xiao
- grid.452859.70000 0004 6006 3273Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong China
| | - Qiu-Nuo Li
- grid.452859.70000 0004 6006 3273Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong China
| | - Xiao-Shuai Ren
- grid.452859.70000 0004 6006 3273Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong China
| | - Zhi-Gang Liu
- grid.284723.80000 0000 8877 7471Cancer Center, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, Guangdong China
| | - Bo-Wen Hu
- grid.452859.70000 0004 6006 3273Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong China
| | - Hong-Sheng Wang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Hao Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
| | - Guan-Min Jiang
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
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13
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Chaitanya NSN, Tammineni P, Nagaraju GP, Reddy ABM. Pleiotropic roles of evolutionarily conserved signaling intermediate in toll pathway (ECSIT) in pathophysiology. J Cell Physiol 2022; 237:3496-3504. [DOI: 10.1002/jcp.30832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 06/23/2022] [Accepted: 07/04/2022] [Indexed: 11/10/2022]
Affiliation(s)
- Nyshadham S. N. Chaitanya
- Department of Animal Biology, School of Life Sciences University of Hyderabad Hyderabad Telangana India
| | - Prasad Tammineni
- Department of Animal Biology, School of Life Sciences University of Hyderabad Hyderabad Telangana India
| | | | - Aramati BM Reddy
- Department of Animal Biology, School of Life Sciences University of Hyderabad Hyderabad Telangana India
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14
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Song L, Liu S, Zhao S. Everolimus (RAD001) combined with programmed death-1 (PD-1) blockade enhances radiosensitivity of cervical cancer and programmed death-ligand 1 (PD-L1) expression by blocking the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) pathway. Bioengineered 2022; 13:11240-11257. [PMID: 35485300 PMCID: PMC9208494 DOI: 10.1080/21655979.2022.2064205] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cervical cancer (CC) is the 4th most prevalent malignancy in females. This study explored the mechanism of everolimus (RAD001) combined with programmed death-1 (PD-1) blockade on radiosensitivity by phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and autophagy in CC cells. Low-radiosensitive CaSki cells were selected as study objects. After RAD001 treatment, PI3K/AKT/mTOR pathway activation, autophagy, migration and invasion abilities, autophagy-related proteins (LC3-I, LC3-II, and p62), and PD-L1 expression in CC cells were detected. After triple treatment of radiotherapy (RT), RAD001, and PD-1 blockade to the CC mouse models, tumor weight and volume were recorded. Ki67 expression, the number of CD8 + T cells, and the ability to produce IFN-γ and TNF-α in tumor tissues were determined. RAD001 promoted autophagy by repressing PI3K/AKT/mTOR pathway, augmented RT-induced apoptosis, and weakened migration and invasion, thereby increasing CC cell radiosensitivity. RAD001 elevated RT-induced PD-L1 level. RT combined with RAD001 and PD-1 blockade intensified the inhibitory effect of RT on tumor growth, reduced the amount of Ki67-positive cells, enhanced radiosensitivity of CC mice, and increased the quantity and killing ability of CD8 + T cells. Briefly, RAD001 combined with PD-1 blockade increases radiosensitivity of CC by impeding the PI3K/AKT/mTOR pathway and potentiating cell autophagy.
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Affiliation(s)
- Lili Song
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shikai Liu
- Department of Obstetrics and Gynecology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Sufen Zhao
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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15
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Kim MJ, Min Y, Jeong SK, Son J, Kim JY, Lee JS, Kim DH, Lee JS, Chun E, Lee KY. USP15 negatively regulates lung cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction. Cell Death Dis 2022; 13:348. [PMID: 35422093 PMCID: PMC9010460 DOI: 10.1038/s41419-022-04808-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 03/17/2022] [Accepted: 03/30/2022] [Indexed: 12/22/2022]
Abstract
TNF receptor-associated factor 6 (TRAF6)-BECN1 signaling axis plays a pivotal role in autophagy induction through ubiquitination of BECN1, thereby inducing lung cancer migration and invasion in response to toll-like receptor 4 (TLR4) stimulation. Herein, we provide novel molecular and cellular mechanisms involved in the negative effect of ubiquitin-specific peptidase 15 (USP15) on lung cancer progression. Clinical data of the TCGA and primary non-small cell lung cancer (NSCLC) patients (n = 41) revealed that the expression of USP15 was significantly downregulated in lung cancer patients. Importantly, USP15-knockout (USP15KO) A549 and USP15KO H1299 lung cancer cells generated with CRISPR-Cas9 gene-editing technology showed increases in cancer migration and invasion with enhanced autophagy induction in response to TLR4 stimulation. In addition, biochemical studies revealed that USP15 interacted with BECN1, but not with TRAF6, and induced deubiquitination of BECN1, thereby attenuating autophagy induction. Notably, in primary NSCLC patients (n = 4) with low expression of USP15, 10 genes (CCNE1, MMP9, SFN, UBE2C, CCR2, FAM83A, ETV4, MYO7A, MMP11, and GSDMB) known to promote lung cancer progression were significantly upregulated, whereas 10 tumor suppressor genes (FMO2, ZBTB16, FCN3, TCF21, SFTPA1B, HPGD, SOSTDC1, TMEM100, GDF10, and WIF1) were downregulated, providing clinical relevance of the functional role of USP15 in lung cancer progression. Taken together, our data demonstrate that USP15 can negatively regulate the TRAF6-BECN1 signaling axis for autophagy induction. Thus, USP15 is implicated in lung cancer progression.
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Affiliation(s)
- Mi-Jeong Kim
- Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Yoon Min
- Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Soo-Kyung Jeong
- R&D Center, CHA Vaccine Institute, Seongnam-si, 13493, Republic of Korea
| | - Juhee Son
- Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Ji Young Kim
- Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Ji Su Lee
- Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Duk-Hwan Kim
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
- Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Joo Sang Lee
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Eunyoung Chun
- R&D Center, CHA Vaccine Institute, Seongnam-si, 13493, Republic of Korea.
| | - Ki-Young Lee
- Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
- Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Samsung Medical Center, Sungkyunkwan University, Seoul, 06351, Republic of Korea.
- Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
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16
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The Critical Role of Toll-like Receptor-mediated Signaling in Cancer Immunotherapy. MEDICINE IN DRUG DISCOVERY 2022. [DOI: 10.1016/j.medidd.2022.100122] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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17
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Kim MJ, Choi B, Kim JY, Min Y, Kwon DH, Son J, Lee JS, Lee JS, Chun E, Lee KY. USP8 regulates liver cancer progression via the inhibition of TRAF6-mediated signal for NF-κB activation and autophagy induction by TLR4. Transl Oncol 2022; 15:101250. [PMID: 34688043 PMCID: PMC8546492 DOI: 10.1016/j.tranon.2021.101250] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Herein, we aimed to elucidate the molecular and cellular mechanism in which ubiquitin-specific protease 8 (USP8) is implicated in liver cancer progression via TRAF6-mediated signal. USP8 induces the deubiquitination of TRAF6, TAB2, TAK1, p62, and BECN1, which are pivotal roles for NF-κB activation and autophagy induction. Notably, the LIHC patient with low USP8 mRNA expression showed markedly shorter survival time, whereas there was no significant difference in the other 18-human cancers. Importantly, the TCGA data analysis on LIHC and transcriptome analysis on the USP8 knockout (USP8KO) SK-HEP-1 cells revealed a significant correlation between USP8 and TRAF6, TAB2, TAK1, p62, and BECN1, and enhanced NF-κB-dependent and autophagy-related cancer progression/metastasis-related genes in response to LPS stimulation. Furthermore, USP8KO SK-HEP-1 cells showed an increase in cancer migration and invasion by TLR4 stimulation, and a marked increase of tumorigenicity and metastasis in xenografted NSG mice. The results demonstrate that USP8 is negatively implicated in the LIHC progression through the regulation of TRAF6-mediated signal for the activation of NF-κB activation and autophagy induction. Our findings provide useful insight into the LIHC pathogenesis of cancer progression.
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Affiliation(s)
- Mi-Jeong Kim
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Bongkum Choi
- Department of Medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Ji Young Kim
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Yoon Min
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Do Hee Kwon
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Juhee Son
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Ji Su Lee
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Joo Sang Lee
- Department of Precision medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Eunyoung Chun
- CHA Vaccine Institute, 560 Dunchon-daero, Jungwon-gu, Seongnam-si, Gyeonggi-do 13230, Republic of Korea.
| | - Ki-Young Lee
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea.
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18
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Son J, Kim MJ, Lee JS, Kim JY, Chun E, Lee KY. Hepatitis B virus X Protein Promotes Liver Cancer Progression through Autophagy Induction in Response to TLR4 Stimulation. Immune Netw 2021; 21:e37. [PMID: 34796041 PMCID: PMC8568915 DOI: 10.4110/in.2021.21.e37] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/28/2021] [Accepted: 10/20/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus X (HBx) protein has been reported as a key protein regulating the pathogenesis of HBV-induced hepatocellular carcinoma (HCC). Recent evidence has shown that HBx is implicated in the activation of autophagy in hepatic cells. Nevertheless, the precise molecular and cellular mechanism by which HBx induces autophagy is still controversial. Herein, we investigated the molecular and cellular mechanism by which HBx is involved in the TRAF6-BECN1-Bcl-2 signaling for the regulation of autophagy in response to TLR4 stimulation, therefore influencing the HCC progression. HBx interacts with BECN1 (Beclin 1) and inhibits the association of the BECN1-Bcl-2 complex, which is known to prevent the assembly of the pre-autophagosomal structure. Furthermore, HBx enhances the interaction between VPS34 and TRAF6-BECN1 complex, increases the ubiquitination of BECN1, and subsequently enhances autophagy induction in response to LPS stimulation. To verify the functional role of HBx in liver cancer progression, we utilized different HCC cell lines, HepG2, SK-Hep-1, and SNU-761. HBx-expressing HepG2 cells exhibited enhanced cell migration, invasion, and cell mobility in response to LPS stimulation compared to those of control HepG2 cells. These results were consistently observed in HBx-expressed SK-Hep-1 and HBx-expressed SNU-761 cells. Taken together, our findings suggest that HBx positively regulates the induction of autophagy through the inhibition of the BECN1-Bcl-2 complex and enhancement of the TRAF6-BECN1-VPS34 complex, leading to enhance liver cancer migration and invasion.
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Affiliation(s)
- Juhee Son
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Mi-Jeong Kim
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Ji Su Lee
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Ji Young Kim
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | | | - Ki-Young Lee
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Korea
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19
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Tang J, Li Y, Xia S, Li J, Yang Q, Ding K, Zhang H. Sequestosome 1/p62: A multitasker in the regulation of malignant tumor aggression (Review). Int J Oncol 2021; 59:77. [PMID: 34414460 PMCID: PMC8425587 DOI: 10.3892/ijo.2021.5257] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
Sequestosome 1 (SQSTM1)/p62 is an adapter protein mainly involved in the transportation, degradation and destruction of various proteins that cooperates with components of autophagy and the ubiquitin‑proteasome degradation pathway. Numerous studies have shown that SQSTM1/p62 functions at multiple levels, including involvement in genetic stability or modification, post‑transcriptional regulation and protein function. As a result, SQSTM1/p62 is a versatile protein that is a critical core regulator of tumor cell genetic stability, autophagy, apoptosis and other forms of cell death, malignant growth, proliferation, migration, invasion, metastasis and chemoradiotherapeutic response, and an indicator of patient prognosis. SQSTM1/p62 regulates these processes via its distinct molecular structure, through which it participates in a variety of activating or inactivating tumor‑related and tumor microenvironment‑related signaling pathways, particularly positive feedback loops and epithelial‑mesenchymal transition‑related pathways. Therefore, functioning as a proto‑oncogene or tumor suppressor gene in various types of cancer and tumor‑associated microenvironments, SQSTM1/p62 is capable of promoting or retarding malignant tumor aggression, giving rise to immeasurable effects on tumor occurrence and development, and on patient treatment and prognosis.
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Affiliation(s)
- Jinlong Tang
- Department of Pathology and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Yuan Li
- Department of Pediatrics, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310000, P.R. China
| | - Shuli Xia
- Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang 310058, P.R. China
- Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang 310058, P.R. China
| | - Jinfan Li
- Department of Pathology and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Qi Yang
- Department of Pathology and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Kefeng Ding
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
- Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Honghe Zhang
- Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang 310058, P.R. China
- Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang 310058, P.R. China
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20
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Crosstalk between Autophagy and Inflammatory Processes in Cancer. Life (Basel) 2021; 11:life11090903. [PMID: 34575052 PMCID: PMC8466094 DOI: 10.3390/life11090903] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/25/2021] [Accepted: 08/28/2021] [Indexed: 12/18/2022] Open
Abstract
Inflammation is an adaptive response to tissue injury, which is a critical process in order to restore tissue functionality and homeostasis. The association between inflammation and cancer has been a topic of interest for many years, not only inflammatory cells themselves but also the chemokines and cytokines they produce, which affect cancer development. Autophagy is an intracellular self-degradative process providing elimination of damaged or dysfunctional organelles under stressful conditions such as nutrient deficiency, hypoxia, or chemotherapy. Interestingly, the signaling pathways that are involved in cancer-associated inflammation may regulate autophagy as well. These are (1) the toll-like receptor (TLR) signaling cascade, (2) the reactive oxygen species (ROS) signaling pathway, (3) the inflammatory cytokine signaling pathway, and (4) the IκB kinase (IKK)/Nuclear factor-κB (NF-κB) signaling axis. Moreover, the studies on the context-specific functions of autophagy during inflammatory responses in cancer will be discussed here. On that basis, we focus on autophagy inhibitors and activators regulating inflammatory process in cancer as useful candidates for enhancing anticancer effects. This review summarizes how the autophagic process regulates these key inflammatory processes and vice versa in various cancers.
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21
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Cai X, Zou F, Xuan R, Lai XY. Exosomes from mesenchymal stem cells expressing microribonucleic acid-125b inhibit the progression of diabetic nephropathy via the tumour necrosis factor receptor-associated factor 6/Akt axis. Endocr J 2021; 68:817-828. [PMID: 34024846 DOI: 10.1507/endocrj.ej20-0619] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Diabetic nephropathy (DN) seriously threatens the health of patients with diabetes. Moreover, it has been reported that mesenchymal stem cell (MSC)-derived exosomal miRNAs can modulate the progression of multiple diseases, including DN. It has been suggested that miR-125b is involved in DN. However, the biological functions of exosomal miRNAs, especially miR-125b, in DN are still unclear. To establish a DN model in vitro, we used a model of human embryonic kidney epithelial cells (HKCs) injury induced by high glucose (HG). Then, miR-125b was delivered to the model cells in vitro via MSC-derived exosomes (MSC-Exos), and the effect of exosomal miR-125b on HKCs apoptosis was evaluated by flow cytometry. qRT-PCR or western blotting was performed to measure miR-125b or tumour necrosis factor receptor-associated factor 6 (TRAF6) expression in HKC. The effect of MSC-Exos on HKCs apoptosis after miR-125b knockdown was determined by flow cytometry. Moreover, dual-luciferase reporter assays were used to determine the targeting relationship between miR-125b and TRAF6 in HKCs. Our data revealed that MSC-Exos increased HG-induced autophagy in HKCs and reversed HKCs apoptosis. Moreover, our study found that miR-125b was enriched in MSC-Exos and directly targeted TRAF6 in HKCs. In addition, exosomally transferred miR-125b inhibited the apoptosis of HG-treated HKCs by mediating Akt signalling. In summary, MSC-derived exosomal miR-125b induced autophagy and inhibited apoptosis in HG-treated HKCs via the downregulation of TRAF6. Therefore, our study provided a new idea for DN treatment.
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Affiliation(s)
- Xia Cai
- Department of Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, P.R.China
| | - Fang Zou
- Department of Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, P.R.China
| | - Rui Xuan
- Department of Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, P.R.China
| | - Xiao-Yang Lai
- Department of Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, P.R.China
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22
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El-Malkey NF, Alsemeh AE, Ashour WM, Hassan NH, Edrees HM. Fetuin-A exerts a protective effect against experimentally induced intestinal ischemia/reperfusion by suppressing autophagic cell death. Exp Biol Med (Maywood) 2021; 246:1307-1317. [PMID: 33653159 DOI: 10.1177/1535370221995207] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Intestinal tissue is highly susceptible to ischemia/reperfusion injury in many hazardous health conditions. The anti-inflammatory and antioxidant glycoprotein fetuin-A showed efficacy in cerebral ischemic injury; however, its protective role against intestinal ischemia/reperfusion remains elusive. Therefore, this study investigated the protective role of fetuin-A supplementation against intestinal structural changes and dysfunction in a rat model of intestinal ischemia/reperfusion. We equally divided 72 male rats into control, sham, ischemia/reperfusion, and fetuin-A-pretreated ischemia/reperfusion (100 mg/kg/day fetuin-A intraperitoneally for three days prior to surgery and a third dose 1 h prior to the experiment) groups. After 2 h of reperfusion, the jejunum was dissected and examined for spontaneous contractility. A jejunal homogenate was used to assess inflammatory and oxidative stress enzymes. Staining of histological sections was carried out with hematoxylin, eosin and Masson's trichrome stain for evaluation. Immunohistochemistry was performed to detect autophagy proteins beclin-1, LC3, and p62. This study found that fetuin-A significantly improved ischemia/reperfusion-induced mucosal injury by reducing the percentage of areas of collagen deposition, increasing the amplitude of spontaneous contraction, decreasing inflammation and oxidative stress, and upregulating p62 expression, which was accompanied by beclin-1 and LC3 downregulation. Our findings suggest that fetuin-A treatment can prevent ischemia/reperfusion-induced jejunal structural and functional changes by increasing antioxidant activity and regulating autophagy disturbances observed in the ischemia/reperfusion rat model. Furthermore, fetuin-A may provide a protective influence against intestinal ischemia/reperfusion complications.
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Affiliation(s)
- Nanees F El-Malkey
- Medical Physiology Department, Faculty of Medicine, Zagazig University, Al-Sharqia 44519, Egypt
| | - Amira E Alsemeh
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Al-Sharqia 44519, Egypt
| | - Wesam Mr Ashour
- Medical Physiology Department, Faculty of Medicine, Zagazig University, Al-Sharqia 44519, Egypt
| | - Nancy H Hassan
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Al-Sharqia 44519, Egypt
| | - Husam M Edrees
- Medical Physiology Department, Faculty of Medicine, Zagazig University, Al-Sharqia 44519, Egypt.,Department of Public Health, College of Public Health and Health Informatics, Qassim University, Al Bukairiyah 51941, Saudi Arabia
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23
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Role of Hypoxia-Mediated Autophagy in Tumor Cell Death and Survival. Cancers (Basel) 2021; 13:cancers13030533. [PMID: 33573362 PMCID: PMC7866864 DOI: 10.3390/cancers13030533] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 12/14/2022] Open
Abstract
Programmed cell death or type I apoptosis has been extensively studied and its contribution to the pathogenesis of disease is well established. However, autophagy functions together with apoptosis to determine the overall fate of the cell. The cross talk between this active self-destruction process and apoptosis is quite complex and contradictory as well, but it is unquestionably decisive for cell survival or cell death. Autophagy can promote tumor suppression but also tumor growth by inducing cancer-cell development and proliferation. In this review, we will discuss how autophagy reprograms tumor cells in the context of tumor hypoxic stress. We will illustrate how autophagy acts as both a suppressor and a driver of tumorigenesis through tuning survival in a context dependent manner. We also shed light on the relationship between autophagy and immune response in this complex regulation. A better understanding of the autophagy mechanisms and pathways will undoubtedly ameliorate the design of therapeutics aimed at targeting autophagy for future cancer immunotherapies.
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24
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Nazarko TY. Special Issue on "Ubiquitin and Autophagy". Cells 2021; 10:cells10010116. [PMID: 33435134 PMCID: PMC7827787 DOI: 10.3390/cells10010116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 01/05/2021] [Indexed: 11/16/2022] Open
Affiliation(s)
- Taras Y Nazarko
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA
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25
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Macrophage Autophagy and Silicosis: Current Perspective and Latest Insights. Int J Mol Sci 2021; 22:ijms22010453. [PMID: 33466366 PMCID: PMC7795780 DOI: 10.3390/ijms22010453] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 12/31/2020] [Accepted: 12/31/2020] [Indexed: 12/16/2022] Open
Abstract
Silicosis is an urgent public health problem in many countries. Alveolar macrophage (AM) plays an important role in silicosis progression. Autophagy is a balanced mechanism for regulating the cycle of synthesis and degradation of cellular components. Our previous study has shown that silica engulfment results in lysosomal rupture, which may lead to the accumulation of autophagosomes in AMs of human silicosis. The excessive accumulation of autophagosomes may lead to apoptosis in AMs. Herein, we addressed some assumptions concerning the complex function of autophagy-related proteins on the silicosis pathogenesis. We also recapped the molecular mechanism of several critical proteins targeting macrophage autophagy in the process of silicosis fibrosis. Furthermore, we summarized several exogenous chemicals that may cause an aggravation or alleviation for silica-induced pulmonary fibrosis by regulating AM autophagy. For example, lipopolysaccharides or nicotine may have a detrimental effect combined together with silica dust via exacerbating the blockade of AM autophagic degradation. Simultaneously, some natural product ingredients such as atractylenolide III, dioscin, or trehalose may be the potential AM autophagy regulators, protecting against silicosis fibrosis. In conclusion, the deeper molecular mechanism of these autophagy targets should be explored in order to provide feasible clues for silicosis therapy in the clinical setting.
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26
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Broad and Complex Roles of NBR1-Mediated Selective Autophagy in Plant Stress Responses. Cells 2020; 9:cells9122562. [PMID: 33266087 PMCID: PMC7760648 DOI: 10.3390/cells9122562] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 11/27/2020] [Accepted: 11/27/2020] [Indexed: 02/07/2023] Open
Abstract
Selective autophagy is a highly regulated degradation pathway for the removal of specific damaged or unwanted cellular components and organelles such as protein aggregates. Cargo selectivity in selective autophagy relies on the action of cargo receptors and adaptors. In mammalian cells, two structurally related proteins p62 and NBR1 act as cargo receptors for selective autophagy of ubiquitinated proteins including aggregation-prone proteins in aggrephagy. Plant NBR1 is the structural and functional homolog of mammalian p62 and NBR1. Since its first reports almost ten years ago, plant NBR1 has been well established to function as a cargo receptor for selective autophagy of stress-induced protein aggregates and play an important role in plant responses to a broad spectrum of stress conditions including heat, salt and drought. Over the past several years, important progress has been made in the discovery of specific cargo proteins of plant NBR1 and their roles in the regulation of plant heat stress memory, plant-viral interaction and special protein secretion. There is also new evidence for a possible role of NBR1 in stress-induced pexophagy, sulfur nutrient responses and abscisic acid signaling. In this review, we summarize these progresses and discuss the potential significance of NBR1-mediated selective autophagy in broad plant responses to both biotic and abiotic stresses.
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27
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Bustos SO, Antunes F, Rangel MC, Chammas R. Emerging Autophagy Functions Shape the Tumor Microenvironment and Play a Role in Cancer Progression - Implications for Cancer Therapy. Front Oncol 2020; 10:606436. [PMID: 33324568 PMCID: PMC7724038 DOI: 10.3389/fonc.2020.606436] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 10/22/2020] [Indexed: 12/15/2022] Open
Abstract
The tumor microenvironment (TME) is a complex environment where cancer cells reside and interact with different types of cells, secreted factors, and the extracellular matrix. Additionally, TME is shaped by several processes, such as autophagy. Autophagy has emerged as a conserved intracellular degradation pathway for clearance of damaged organelles or aberrant proteins. With its central role, autophagy maintains the cellular homeostasis and orchestrates stress responses, playing opposite roles in tumorigenesis. During tumor development, autophagy also mediates autophagy-independent functions associated with several hallmarks of cancer, and therefore exerting several effects on tumor suppression and/or tumor promotion mechanisms. Beyond the concept of degradation, new different forms of autophagy have been described as modulators of cancer progression, such as secretory autophagy enabling intercellular communication in the TME by cargo release. In this context, the synthesis of senescence-associated secretory proteins by autophagy lead to a senescent phenotype. Besides disturbing tumor treatment responses, autophagy also participates in innate and adaptive immune signaling. Furthermore, recent studies have indicated intricate crosstalk between autophagy and the epithelial-mesenchymal transition (EMT), by which cancer cells obtain an invasive phenotype and metastatic potential. Thus, autophagy in the cancer context is far broader and complex than just a cell energy sensing mechanism. In this scenario, we will discuss the key roles of autophagy in the TME and surrounding cells, contributing to cancer development and progression/EMT. Finally, the potential intervention in autophagy processes as a strategy for cancer therapy will be addressed.
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Affiliation(s)
- Silvina Odete Bustos
- Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina de São Paulo, Brazil
| | - Fernanda Antunes
- Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina de São Paulo, Brazil
| | - Maria Cristina Rangel
- Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina de São Paulo, Brazil
| | - Roger Chammas
- Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina de São Paulo, Brazil
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28
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AMPKα1 Regulates Lung and Breast Cancer Progression by Regulating TLR4-Mediated TRAF6-BECN1 Signaling Axis. Cancers (Basel) 2020; 12:cancers12113289. [PMID: 33172060 PMCID: PMC7694660 DOI: 10.3390/cancers12113289] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 12/21/2022] Open
Abstract
Simple Summary TRAF6-BECN1 signaling axis in TLR4 signal plays an essential role for the autophagy induction, thereby it regulates cancer migration and invasion. Here we show that AMPKα1, one of the isoforms of AMPK, is functionally involved in autophagy induction by regulating the TRAF6-BECN1 signaling axis. In this context, AMPKα1-knockout lung or breast cancer cells exhibited the attenuation of cancer cell migration and invasion induced by TLR4 simulation. Additionally, we could find that the expression of AMPKα1 is positively associated with gene expressions related to autophagy, migration, and metastasis of cancer cells in primary non-small cell lung cancers (NSCLCs). These findings demonstrate that AMPKα1 plays a pivotal role in cancer progression by regulating the TRAF6-BECN1 signaling axis for autophagy induction. Abstract TRAF6-BECN1 signaling axis is critical for autophagy induction and functionally implicated in cancer progression. Here, we report that AMP-activated protein kinase alpha 1 (AMPKα1, PRKAA1) is positively involved in autophagy induction and cancer progression by regulating TRAF6-BECN1 signaling axis. Mechanistically, AMPKα1 interacted with TRAF6 and BECN1. It also enhanced ubiquitination of BECN1 and autophagy induction. AMPKα1-knockout (AMPKα1KO) HEK293T or AMPKα1-knockdown (AMPKα1KD) THP-1 cells showed impaired autophagy induced by serum starvation or TLR4 (Toll-like receptor 4) stimulation. Additionally, AMPKα1KD THP-1 cells showed decreases of autophagy-related and autophagosome-related genes induced by TLR4. AMPKα1KO A549 cells exhibited attenuation of cancer migration and invasion induced by TLR4. Moreover, primary non-small cell lung cancers (NSCLCs, n = 6) with low AMPKαl levels showed markedly decreased expression of genes related to autophagy, cell migration and adhesion/metastasis, inflammation, and TLRs whereas these genes were significantly upregulated in NSCLCs (n = 5) with high AMPKαl levels. Consistently, attenuation of cancer migration and invasion could be observed in AMPKα1KO MDA-MB-231 and AMPKα1KO MCF-7 human breast cancer cells. These results suggest that AMPKα1 plays a pivotal role in cancer progression by regulating the TRAF6-BECN1 signaling axis for autophagy induction.
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