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Nie AY, Xiao ZH, Deng JL, Li N, Hao LY, Li SH, Hu XY. Bidirectional regulation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon gene pathway and its impact on hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:98556. [PMID: 39958554 PMCID: PMC11755995 DOI: 10.4251/wjgo.v17.i2.98556] [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: 06/29/2024] [Revised: 10/30/2024] [Accepted: 11/18/2024] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) ranks as the fourth leading cause of cancer-related deaths in China, and the treatment options are limited. The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) activates the stimulator of interferon gene (STING) signaling pathway as a crucial immune response pathway in the cytoplasm, which detects cytoplasmic DNA to regulate innate and adaptive immune responses. As a potential therapeutic target, cGAS-STING pathway markedly inhibits tumor cell proliferation and metastasis, with its activation being particularly relevant in HCC. However, prolonged pathway activation may lead to an immunosuppressive tumor microenvironment, which fostering the invasion or metastasis of liver tumor cells. AIM To investigate the dual-regulation mechanism of cGAS-STING in HCC. METHODS This review was conducted according to the PRISMA guidelines. The study conducted a comprehensive search for articles related to HCC on PubMed and Web of Science databases. Through rigorous screening and meticulous analysis of the retrieved literature, the research aimed to summarize and elucidate the impact of the cGAS-STING pathway on HCC tumors. RESULTS All authors collaboratively selected studies for inclusion, extracted data, and the initial search of online databases yielded 1445 studies. After removing duplicates, the remaining 964 records were screened. Ultimately, 55 articles met the inclusion criteria and were included in this review. CONCLUSION Acute inflammation can have a few inhibitory effects on cancer, while chronic inflammation generally promotes its progression. Extended cGAS-STING pathway activation will result in a suppressive tumor microenvironment.
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Affiliation(s)
- Ai-Yu Nie
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Zhong-Hui Xiao
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Jia-Li Deng
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Na Li
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Li-Yuan Hao
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Sheng-Hao Li
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Xiao-Yu Hu
- Department of Infection, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
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2
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Du L, Zhang Q, Li Y, Li T, Deng Q, Jia Y, Lei K, Kan D, Xie F, Huang S. Research progress on the role of PTEN deletion or mutation in the immune microenvironment of glioblastoma. Front Oncol 2024; 14:1409519. [PMID: 39206155 PMCID: PMC11349564 DOI: 10.3389/fonc.2024.1409519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
Recent advances in immunotherapy represent a breakthrough in solid tumor treatment but the existing data indicate that immunotherapy is not effective in improving the survival time of patients with glioblastoma. The tumor microenvironment (TME) exerts a series of inhibitory effects on immune effector cells, which limits the clinical application of immunotherapy. Growing evidence shows that phosphate and tension homology deleted on chromosome ten (PTEN) plays an essential role in TME immunosuppression of glioblastoma. Emerging evidence also indicates that targeting PTEN can improve the anti-tumor immunity in TME and enhance the immunotherapy effect, highlighting the potential of PTEN as a promising therapeutic target. This review summarizes the function and specific upstream and downstream targets of PTEN-associated immune cells in glioblastoma TME, providing potential drug targets and therapeutic options for glioblastoma.
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Affiliation(s)
- Leiya Du
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Qian Zhang
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Yi Li
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Ting Li
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Qingshan Deng
- Department of Neurosurgery, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Yuming Jia
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Kaijian Lei
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Daohong Kan
- Department of Burn and Plastic Surgery, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Fang Xie
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
| | - Shenglan Huang
- Department of Oncology, The Second People’s Hospital of Yibin, Yibin, Sichuan, China
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Saw PE, Liu Q, Wong PP, Song E. Cancer stem cell mimicry for immune evasion and therapeutic resistance. Cell Stem Cell 2024; 31:1101-1112. [PMID: 38925125 DOI: 10.1016/j.stem.2024.06.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 03/11/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024]
Abstract
Cancer stem cells (CSCs) are heterogeneous, possess self-renewal attributes, and orchestrate important crosstalk in tumors. We propose that the CSC state represents "mimicry" by cancer cells that leads to phenotypic plasticity. CSC mimicry is suggested as CSCs can impersonate immune cells, vasculo-endothelia, or lymphangiogenic cells to support cancer growth. CSCs facilitate both paracrine and juxtracrine signaling to prime tumor-associated immune and stromal cells to adopt pro-tumoral phenotypes, driving therapeutic resistance. Here, we outline the ingenuity of CSCs' mimicry in their quest to evade immune detection, which leads to immunotherapeutic resistance, and highlight CSC-mimicry-targeted therapeutic strategies for robust immunotherapy.
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Affiliation(s)
- Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan, China
| | - Qiang Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ping-Pui Wong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan, China
| | - Erwei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan, China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Zenith Institute of Medical Sciences, Guangzhou 510120, China.
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4
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Abd El-Aziz YS, Toit-Thompson TD, McKay MJ, Molloy MP, Stoner S, McDowell B, Moon E, Sioson L, Sheen A, Chou A, Gill AJ, Jansson PJ, Sahni S. Novel combinatorial autophagy inhibition therapy for triple negative breast cancers. Eur J Pharmacol 2024; 973:176568. [PMID: 38604544 DOI: 10.1016/j.ejphar.2024.176568] [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: 11/02/2023] [Revised: 04/04/2024] [Accepted: 04/04/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer subtypes. It is characterized by lack of estrogen, progesterone and human epidermal growth factor 2 receptors, and thus, have limited therapeutic options. Autophagy has been found to be correlated with poor prognosis and aggressive behaviour in TNBC. This study aimed to target autophagy in TNBC via a novel approach to inhibit TNBC progression. METHODS Immunoblotting and confocal microscopy were carried out to examine the effect of tumor microenvironmental stressors on autophagy. Cellular proliferation and migration assays were used to test the effect of different autophagy inhibitors and standard chemotherapy alone or in combination. In vivo xenograft mouse model was utilized to assess the effect of autophagy inhibitors alone or in combination with Paclitaxel. High resolution mass spectrometry based proteomic analysis was performed to explore the mechanisms behind chemoresistance in TNBC. Lastly, immunohistochemistry was done to assess the correlation between autophagy related proteins and clinical characteristics in TNBC tissue specimens. RESULTS Metabolic stressors were found to induce autophagy in TNBC cell lines. Autophagy initiation inhibitors, SAR405 and MRT68921, showed marked synergy in their anti-proliferative activity in both chemosensitive and chemoresistant TNBC cell models. Paradoxically, positive expression of autophagosome marker LC3 was shown to be associated with better overall survival of TNBC patients. CONCLUSION In this study, a novel combination between different autophagy inhibitors was identified which inhibited tumor cell proliferation in both chemosensitive and chemoresistant TNBC cells and could result in development of a novel treatment modality against TNBC.
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Affiliation(s)
- Yomna S Abd El-Aziz
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Taymin du Toit-Thompson
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia
| | - Matthew J McKay
- Kolling Institute of Medical Research, University of Sydney, Australia
| | - Mark P Molloy
- Kolling Institute of Medical Research, University of Sydney, Australia
| | - Shihani Stoner
- Kolling Institute of Medical Research, University of Sydney, Australia
| | - Betty McDowell
- NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
| | - Elizabeth Moon
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia
| | - Loretta Sioson
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
| | - Amy Sheen
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
| | - Angela Chou
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
| | - Anthony J Gill
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
| | - Patric J Jansson
- Kolling Institute of Medical Research, University of Sydney, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Sumit Sahni
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia.
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Ungurianu A, Zanfirescu A, Margină D. Exploring the therapeutic potential of quercetin: A focus on its sirtuin-mediated benefits. Phytother Res 2024; 38:2361-2387. [PMID: 38429891 DOI: 10.1002/ptr.8168] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/12/2023] [Accepted: 11/20/2023] [Indexed: 03/03/2024]
Abstract
As the global population ages, preventing lifestyle- and aging-related diseases is increasing, necessitating the search for safe and affordable therapeutic interventions. Among nutraceuticals, quercetin, a flavonoid ubiquitously present in various plants, has garnered considerable interest. This review aimed to collate and analyze existing literature on the therapeutic potentials of quercetin, especially its interactions with SIRTs and its clinical applicability based on its bioavailability and safety. This narrative review was based on a literature survey spanning from 2015 to 2023 using PUBMED. The keywords and MeSH terms used were: "quercetin" AND "bioavailability" OR "metabolism" OR "metabolites" as well as "quercetin" AND "SIRTuin" OR "SIRT*" AND "cellular effects" OR "pathway" OR "signaling" OR "neuroprotective" OR "cardioprotective" OR "nephroprotective" OR "antiatherosclerosis" OR "diabetes" OR "antidiabetic" OR "dyslipidemia" AND "mice" OR "rats". Quercetin demonstrates multiple therapeutic activities, including neuroprotective, cardioprotective, and anti-atherosclerotic effects. Its antioxidant, anti-inflammatory, antiviral, and immunomodulatory properties are well-established. At a molecular level, it majorly interacts with SIRTs, particularly SIRT1 and SIRT6, and modulates numerous signaling pathways, contributing to its therapeutic effects. These pathways play roles in reducing oxidative stress, inflammation, autophagy regulation, mitochondrial biogenesis, glucose utilization, fatty acid oxidation, and genome stability. However, clinical trials on quercetin's effectiveness in humans are scarce. Quercetin exhibits a wide range of SIRT-mediated therapeutic effects. Despite the compelling preclinical data, more standardized clinical trials are needed to fully understand its therapeutic potential. Future research should focus on addressing its bioavailability and safety concerns.
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Affiliation(s)
- Anca Ungurianu
- Carol Davila University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Biochemistry, Bucharest, Romania
| | - Anca Zanfirescu
- Faculty of Pharmacy, Department of Pharmacology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Denisa Margină
- Carol Davila University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Biochemistry, Bucharest, Romania
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6
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Abd El-Aziz YS, McKay MJ, Molloy MP, McDowell B, Moon E, Sioson L, Sheen A, Chou A, Gill AJ, Jansson PJ, Sahni S. Inhibition of autophagy initiation: A novel strategy for oral squamous cell carcinomas. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119627. [PMID: 37963518 DOI: 10.1016/j.bbamcr.2023.119627] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/25/2023] [Accepted: 10/31/2023] [Indexed: 11/16/2023]
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) is one of the most common forms of oral cancer and is known to have poor prognostic outcomes. Autophagy is known to be associated with aggressive tumor biology of OSCC. Hence, this study aimed to develop a novel therapeutic strategy against OSCC by targeting the autophagic pathway. METHODS Immunoblotting, and confocal microscopy were used to examine the effect of tumor microenvironmental stressors on the autophagy activity. Cellular proliferation and migration assays were performed to assess the anti-cancer activity of standard chemotherapy and autophagy initiation inhibitors, either alone or in combination. High resolution mass-spectrometry based proteomic analysis was utilized to understand the mechanisms behind chemoresistance in OSCC models. Finally, immunohistochemistry was performed to determine associations between autophagy markers and clinicopathological characteristics. RESULTS Tumor microenvironmental stressors were shown to induce autophagy activity in OSCC cell lines. Novel combinations of chemotherapy and autophagy inhibitors as well as different classes of autophagy inhibitors were identified. Combination of MRT68921 and SAR405 demonstrated marked synergy in their anti-proliferative activity and also showed synergy with chemotherapy in chemoresistant OSCC cell models. Autophagy was identified as one of the key pathways involved in mediating chemoresistance in OSCC. Furthermore, TGM2 was identified as a key upstream regulator of chemoresistance in OSCC models. Finally, positive staining for autophagosome marker LC3 was shown to be associated with low histological grade OSCC. CONCLUSION In conclusion, this study identified a combination of novel autophagy inhibitors which can potently inhibit proliferation of both chemosensitive as well as chemoresistant OSCC cells and could be developed as a novel therapy against advanced OSCC tumors.
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Affiliation(s)
- Yomna S Abd El-Aziz
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Matthew J McKay
- Kolling Institute of Medical Research, University of Sydney, Australia
| | - Mark P Molloy
- Kolling Institute of Medical Research, University of Sydney, Australia
| | - Betty McDowell
- NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
| | - Elizabeth Moon
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia
| | - Loretta Sioson
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
| | - Amy Sheen
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
| | - Angela Chou
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
| | - Anthony J Gill
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
| | - Patric J Jansson
- Kolling Institute of Medical Research, University of Sydney, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Sumit Sahni
- Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia.
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Zhang Y, Yang L, Ou Y, Hu R, Du G, Luo S, Wu F, Wang H, Xie Z, Zhang Y, He C, Ma C, Gong T, Zhang L, Zhang Z, Sun X. Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity. Acta Pharm Sin B 2024; 14:350-364. [PMID: 38261817 PMCID: PMC10792967 DOI: 10.1016/j.apsb.2023.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/16/2023] [Accepted: 06/02/2023] [Indexed: 01/25/2024] Open
Abstract
Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.
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Affiliation(s)
- Yongshun Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Lan Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yangsen Ou
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Rui Hu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Guangsheng Du
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Shuang Luo
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Fuhua Wu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Hairui Wang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Zhiqiang Xie
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yu Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Chunting He
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Cheng Ma
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Tao Gong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Ling Zhang
- Med-X Center for Materials, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
| | - Zhirong Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xun Sun
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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8
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Wang X, Zhou L, Wang H, Chen W, Jiang L, Ming G, Wang J. Metabolic reprogramming, autophagy, and ferroptosis: Novel arsenals to overcome immunotherapy resistance in gastrointestinal cancer. Cancer Med 2023; 12:20573-20589. [PMID: 37860928 PMCID: PMC10660574 DOI: 10.1002/cam4.6623] [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: 04/19/2023] [Revised: 09/05/2023] [Accepted: 09/29/2023] [Indexed: 10/21/2023] Open
Abstract
BACKGROUND Gastrointestinal cancer poses a serious health threat owing to its high morbidity and mortality. Although immune checkpoint blockade (ICB) therapies have achieved meaningful success in most solid tumors, the improvement in survival in gastrointestinal cancers is modest, owing to sparse immune response and widespread resistance. Metabolic reprogramming, autophagy, and ferroptosis are key regulators of tumor progression. METHODS A literature review was conducted to investigate the role of the metabolic reprogramming, autophagy, and ferroptosis in immunotherapy resistance of gastrointestinal cancer. RESULTS Metabolic reprogramming, autophagy, and ferroptosis play pivotal roles in regulating the survival, differentiation, and function of immune cells within the tumor microenvironment. These processes redefine the nutrient allocation blueprint between cancer cells and immune cells, facilitating tumor immune evasion, which critically impacts the therapeutic efficacy of immunotherapy for gastrointestinal cancers. Additionally, there exists profound crosstalk among metabolic reprogramming, autophagy, and ferroptosis. These interactions are paramount in anti-tumor immunity, further promoting the formation of an immunosuppressive microenvironment and resistance to immunotherapy. CONCLUSIONS Consequently, it is imperative to conduct comprehensive research on the roles of metabolic reprogramming, autophagy, and ferroptosis in the resistance of gastrointestinal tumor immunotherapy. This understanding will illuminate the clinical potential of targeting these pathways and their regulatory mechanisms to overcome immunotherapy resistance in gastrointestinal cancers.
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Affiliation(s)
- Xiangwen Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Liwen Zhou
- Department of StomatologyThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Hongpeng Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Wei Chen
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Lei Jiang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Guangtao Ming
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Jun Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
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9
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Wang Y, Gao S, Xu Y, Tang Z, Liu S. Characterization of starvation response-related genes for predicting prognosis in breast cancer. Cancer Sci 2023; 114:3144-3161. [PMID: 37199031 PMCID: PMC10394156 DOI: 10.1111/cas.15836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/29/2023] [Accepted: 04/23/2023] [Indexed: 05/19/2023] Open
Abstract
Breast cancer (BRCA) cells typically exist in nutrient-deficient microenvironments and quickly adapt to states with fluctuating nutrient levels. The tumor microenvironment of starvation is intensely related to metabolism and the malignant progression of BRCA. However, the potential molecular mechanism has not been thoroughly scrutinized. As a result, this study aimed to dissect the prognostic implications of mRNAs involved in the starvation response and construct a signature for forecasting the outcomes of BRCA. In this research, we investigated how starvation could affect BRCA cells' propensities for invasion and migration. The effects of autophagy and glucose metabolism mediated by starved stimulation were examined through transwell assays, western blot, and the detection of glucose concentration. A starvation response-related gene (SRRG) signature was ultimately generated by integrated analysis. The risk score was recognized as an independent risk indicator. The nomogram and calibration curves revealed that the model had excellent prediction accuracy. Functional enrichment analysis indicated this signature was significantly enriched in metabolic-related pathways and energy stress-related biological processes. Furthermore, phosphorylated protein expression of the model core gene EIF2AK3 increased after the stimulus of starvation, and EIF2AK3 may play an essential role in the progression of BRCA in the starved microenvironment. To sum up, we constructed and validated a novel SRRG signature that could accurately predict outcomes and may be developed as a therapeutic target for the precise treatment of BRCA.
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Affiliation(s)
- Yuan Wang
- Department of Breast and Thyroid SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
- Laboratory Research CenterThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Shun Gao
- Department of Breast and Thyroid SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
- Laboratory Research CenterThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Yingkun Xu
- Department of Breast and Thyroid SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Zhenrong Tang
- Department of Breast and Thyroid SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Shengchun Liu
- Department of Breast and Thyroid SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
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10
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Chen Z, Chen H, Huang L, Duan B, Dai S, Cai W, Sun M, Jiang Z, Lu R, Jiang Y, Jiang X, Zheng H, Yao Q, Kim K, Lin G, Xie C, Chu M, Chen R, Kou L. ATB 0,+-targeted nanoparticles initiate autophagy suppression to overcome chemoresistance for enhanced colorectal cancer therapy. Int J Pharm 2023:123082. [PMID: 37244464 DOI: 10.1016/j.ijpharm.2023.123082] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 05/13/2023] [Accepted: 05/23/2023] [Indexed: 05/29/2023]
Abstract
Oxaliplatin (OXA) resistance remains the major obstacle to the successful chemotherapy of colorectal cancer (CRC). As a self-protection mechanism, autophagy may contribute to tumor drug resistance, therefore autophagy suppression could be regarded as a possible treatment option in chemotherapy. Cancer cells, especially drug-resistant tumor cells, increase their demand for specific amino acids by expanding exogenous supply and up-regulating de novo synthesis, to meet the needs for excessive proliferation. Therefore, it is possible to inhibit cancer cell proliferation through pharmacologically blocking the entry of amino acid into cancer cells. SLC6A14 (ATB0, +) is an essential amino acid transporter, that is often abnormally up-regulated in most cancer cells. Herein, in this study, we designed oxaliplatin/berbamine-coloaded, ATB0,+-targeted nanoparticles ((O+B)@Trp-NPs) to therapeutically target SLC6A14 (ATB0, +) and inhibit cancer proliferation. The (O+B)@Trp-NPs utilize the surface-modified tryptophan to achieve SLC6A14-targeted delivery of Berbamine (BBM), a compound that is found in a number of plants used in traditional Chinese medicine, which could suppress autolysosome formation though impairing autophagosome-lysosome fusion. We verified the feasibility of this strategy to overcome the OXA resistance during colorectal cancer treatment. The (O+B)@Trp-NPs significantly inhibited the proliferation and decreased the drug resistance of resistant colorectal cancer cells. In vivo, (O+B)@Trp-NPs greatly suppressed the tumor growth in tumor-bearing mice, which is consistent with the in vitro data. This research offers a unique and promising chemotherapeutic treatment for colorectal cancer.
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Affiliation(s)
- Zhiwei Chen
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, Wenzhou 325000, China; Wenzhou key Laboratory of basic science and translational research of radiation oncology, Wenzhou 325027, China; Zhejiang-Hong Kong Precision Theranostics of Thoracic Tumors Joint Laboratory, Wenzhou 325000, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju 61186, Korea
| | - Heyan Chen
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, Wenzhou 325000, China; Wenzhou key Laboratory of basic science and translational research of radiation oncology, Wenzhou 325027, China; Zhejiang-Hong Kong Precision Theranostics of Thoracic Tumors Joint Laboratory, Wenzhou 325000, China
| | - Lihui Huang
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, Wenzhou 325000, China
| | - Baiqun Duan
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, Wenzhou 325000, China
| | - Sheng Dai
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325027, China
| | - Wenjing Cai
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325027, China
| | - Meng Sun
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325027, China
| | - Zhikai Jiang
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, Wenzhou 325000, China
| | - Ruijie Lu
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, Wenzhou 325000, China
| | - Yiling Jiang
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, Wenzhou 325000, China
| | - Xinyu Jiang
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, Wenzhou 325000, China
| | - Hailun Zheng
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, Wenzhou 325000, China
| | - Qing Yao
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Kwonseop Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju 61186, Korea
| | - Guangyong Lin
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325027, China.
| | - Congying Xie
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, Wenzhou 325000, China; Wenzhou key Laboratory of basic science and translational research of radiation oncology, Wenzhou 325027, China; Zhejiang-Hong Kong Precision Theranostics of Thoracic Tumors Joint Laboratory, Wenzhou 325000, China.
| | - Maoping Chu
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325027, China.
| | - Ruijie Chen
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325027, China
| | - Longfa Kou
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, Wenzhou 325000, China; Wenzhou key Laboratory of basic science and translational research of radiation oncology, Wenzhou 325027, China; Zhejiang-Hong Kong Precision Theranostics of Thoracic Tumors Joint Laboratory, Wenzhou 325000, China.
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11
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Műzes G, Sipos F. Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy. Biomedicines 2023; 11:1130. [PMID: 37189748 PMCID: PMC10135912 DOI: 10.3390/biomedicines11041130] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/04/2023] [Accepted: 04/06/2023] [Indexed: 04/11/2023] Open
Abstract
The immune system and autophagy share a functional relationship. Both innate and adaptive immune responses involve autophagy and, depending on the disease's origin and pathophysiology, it may have a detrimental or positive role on autoimmune disorders. As a "double-edged sword" in tumors, autophagy can either facilitate or impede tumor growth. The autophagy regulatory network that influences tumor progression and treatment resistance is dependent on cell and tissue types and tumor stages. The connection between autoimmunity and carcinogenesis has not been sufficiently explored in past studies. As a crucial mechanism between the two phenomena, autophagy may play a substantial role, though the specifics remain unclear. Several autophagy modifiers have demonstrated beneficial effects in models of autoimmune disease, emphasizing their therapeutic potential as treatments for autoimmune disorders. The function of autophagy in the tumor microenvironment and immune cells is the subject of intensive study. The objective of this review is to investigate the role of autophagy in the simultaneous genesis of autoimmunity and malignancy, shedding light on both sides of the issue. We believe our work will assist in the organization of current understanding in the field and promote additional research on this urgent and crucial topic.
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Affiliation(s)
| | - Ferenc Sipos
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary;
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12
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Wei J, Wu X, Wang S, Liu S, Gao X. Spatial heterogeneity and Immune infiltration of cellular lysosomal pathways reveals a new blueprint for tumor heterogeneity in esophageal cancer. Front Endocrinol (Lausanne) 2023; 14:1138457. [PMID: 37091857 PMCID: PMC10113631 DOI: 10.3389/fendo.2023.1138457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/10/2023] [Indexed: 04/08/2023] Open
Abstract
BackgroundEsophageal squamous cell carcinoma (ESCC) is a common Malignant tumor of digestive tract which have a potential association with lysosomal pathway. The purpose of this study was to explore the correlation between lysosome pathway and immune infiltration of ESCC.MethodsThe cell type annotation of ESCC patients and the distribution of their gene markers were analyzed by single cell data. They were also grouped according to the expression of lysosomal pathways. Gene set variation analysis (GSVA) enriched pathway scoring, Cellchat cell communication was performed to demonstrate the tumour-associated pathway scores and interactions of different cell populations. Relevant differential genes were screened, prognostic risk markers were constructed and direct associations of lysosomal pathway-related gene risk scores with immune infiltration and tumour treatment drug sensitivity were assessed by algorithms. In cellular experiments, qPCR and flow cytometry were used to assess the role of the lysosomal pathway gene-MT1X on tumour cell development.ResultsESCC single cell data were annotated into 7 Cluster clusters by t-sne downscaling analysis. Cellchat analysis revealed that the “MIF” cellular communication network is the main communication mode of the lysosomal pathway in ESCC cells. The lysosomal pathway genetic risk model was found to be significantly different from ESCC prognosis in both the training and validation groups. The lysosome pathway gene risk model was associated with treatment resistance in ESCC patients using oncopredict R package. The correlation between the expression of lysosomal-DEG and tumour immune infiltration and immune cell types by the MCPcounter method. Cellular assays showed that the lysosomal pathway gene MT1X was less expressed in oesophageal cancer cells than in normal oesophageal epithelial cells. Knockdown of MT1X significantly promoted the growth rate of oesophageal cancer cells.ConclusionBased on the single cell sequencing technology and transcriptomic analysis, we confirmed that there is a close association between the lysosomal pathway and the immune infiltration and treatment sensitivity of ESCC, which may be a potential target for a new direction of ESCC therapy.
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Affiliation(s)
- Jinxing Wei
- Henan Provincial Chest Hospital, Zhengzhou University, Zhengzhou, China
| | - XiaoMing Wu
- Henan Provincial Chest Hospital, Zhengzhou University, Zhengzhou, China
| | - Shuohao Wang
- Department of Broad Discipline of Computing, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China
| | - Siqing Liu
- The Second Clinical Medical College, Tianjin Medical University, Heping, Tianjin, China
| | - Xia Gao
- Henan Provincial Chest Hospital, Zhengzhou University, Zhengzhou, China
- *Correspondence: Xia Gao,
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13
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Hosseinalizadeh H, Ebrahimi A, Tavakoli A, Monavari SH. Glioblastoma as a Novel Drug Repositioning Target: Updated State. Anticancer Agents Med Chem 2023; 23:1253-1264. [PMID: 36733195 DOI: 10.2174/1871520623666230202163112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/20/2022] [Accepted: 11/22/2022] [Indexed: 02/04/2023]
Abstract
Glioblastoma multiforme (GBM) is an aggressive form of adult brain tumor that can arise from a low-grade astrocytoma. In recent decades, several new conventional therapies have been developed that have significantly improved the prognosis of patients with GBM. Nevertheless, most patients have a limited long-term response to these treatments and survive < 1 year. Therefore, innovative anti-cancer drugs that can be rapidly approved for patient use are urgently needed. One way to achieve accelerated approval is drug repositioning, extending the use of existing drugs for new therapeutic purposes, as it takes less time to validate their biological activity as well as their safety in preclinical models. In this review, a comprehensive analysis of the literature search was performed to list drugs with antiviral, antiparasitic, and antidepressant properties that may be effective in GBM and their putative anti-tumor mechanisms in GBM cells.
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Affiliation(s)
- Hamed Hosseinalizadeh
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Ammar Ebrahimi
- Department of Biomedical Sciences, University of Lausanne, Rue Du Bugnon, Lausanne, Switzerland
| | - Ahmad Tavakoli
- Research Center of Pediatric Infectious Diseases, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
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14
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Jo H, Shim K, Jeoung D. Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance. Int J Mol Sci 2022; 23:ijms23179592. [PMID: 36076996 PMCID: PMC9455701 DOI: 10.3390/ijms23179592] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/18/2022] [Accepted: 08/18/2022] [Indexed: 11/16/2022] Open
Abstract
Histone deacetylases (HDACs) regulate gene expression through the epigenetic modification of chromatin structure. HDAC6, unlike many other HDACs, is present in the cytoplasm. Its deacetylates non-histone proteins and plays diverse roles in cancer cell initiation, proliferation, autophagy, and anti-cancer drug resistance. The development of HDAC6-specific inhibitors has been relatively successful. Mechanisms of HDAC6-promoted anti-cancer drug resistance, cancer cell proliferation, and autophagy are discussed. The relationship between autophagy and anti-cancer drug resistance is discussed. The effects of combination therapy, which includes HDAC6 inhibitors, on the sensitivity of cancer cells to chemotherapeutics and immune checkpoint blockade are presented. A summary of clinical trials involving HDAC6-specific inhibitors is also presented. This review presents HDAC6 as a valuable target for developing anti-cancer drugs.
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15
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Huang S, Zhao Y, Liu J. HIF-1α enhances autophagy to alleviate apoptosis in marginal cells in the stria vascular in neonatal rats under hypoxia. Int J Biochem Cell Biol 2022; 149:106259. [PMID: 35779841 DOI: 10.1016/j.biocel.2022.106259] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 06/20/2022] [Accepted: 06/27/2022] [Indexed: 11/25/2022]
Abstract
In the cochlea, various factors, such as noise, aging, and inflammation, induce hypoxia, resulting in the up-regulation of hypoxia inducible factor-1α (HIF-1α). The role of HIF-1α in hypoxic marginal cells (MCs) of the stria vascularis is unknown. This study examined HIF-1α-mediated autophagy in MCs of neonatal rats and its mechanism of action. We found that an increase in HIF-1α expression was associated with autophagy and apoptosis. Treatment with PX478, a specific inhibitor of HIF-1α, decreased the HIF-1α level, and the degree of autophagy decreased in hypoxic and apoptotic MCs. By contrast, treatment with DMOG, an activator of HIF-1α, increased autophagy and decreased apoptosis. Both PX478 and DMOG had no effect on the apoptotic rate after treatment with 3-methyladenine, an inhibitor of autophagy, indicating that HIF-1α promoted autophagy to protect MCs from hypoxia-induced apoptosis. Lastly, we silenced Bnip3(Bcl-2/adenovirus E1B 19-kDa interacting protein) in MCs to identify the mechanism of action. Our results show that the HIF-1α-BNIP3 pathway mediates the anti-apoptotic effects through an increase in autophagy.
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Affiliation(s)
- Sihan Huang
- Department of Otorhinolaryngology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yanyun Zhao
- Department of Otorhinolaryngology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jun Liu
- Department of Otorhinolaryngology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
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16
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Li Z, Xu B, Sun Y, Zhou L, Tao Y, Hou W, Bao J, Liu J, Fan W. 1α,25(OH) 2D 3(VD3) promotes Raddeanin A-induced anti-proliferative effects on HeLa cell apoptosis and autophagy through negative regulation of HPV18E6-E7/PD-L1/VDR axis. Bioengineered 2022; 13:357-369. [PMID: 34974811 PMCID: PMC8805891 DOI: 10.1080/21655979.2021.2005223] [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] [Indexed: 01/07/2023] Open
Abstract
Raddeanin A (RA) has indicated suppressive effects on various human tumor cells, and insufficient vitamin D was associated with human papillomavirus (HPV) persistence and gynecological tumors. However, combined effects of RA and vitamin D on HPV-positive cells remain elusive. Herein, we aimed to investigate the combined effects of RA and 1ɑ,25(OH)2D3 (VD3) on cellular viability and modulation of HPV18E6/E7, programmed cell death 1 ligand (PD-L1) and vitamin D receptor (VDR) expression in HeLa cells in vitro. HeLa cells were treated with RA alone or VD3 combined with RA. Cell viability was measured using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), and apoptosis was detected by flow cytometry. Real-time PCR (qRT-PCR) and Western blot were used to determine the gene/protein expression levels. The autophagosomes were observed by Transmission electron microscopy (TEM). The result showed that cell viability was inhibited by RA, and apoptosis in HeLa cells treated with RA was elevated accordingly. The expression of Bax, Cleaved-caspase-3, Cleaved-caspase-9 and Cleaved-PARP increased, and Bcl-2 decreased. The autophagy was induced by RA, as evidenced by elevated autophagosomes and the increased LC3-II/I ratio and Beclin-1. The expression of HPV18E6/E7, PD-L1 and VDR was reduced by RA. Moreover, RA combined with VD3 had a stronger effect on HeLa cells than RA alone. In conclusion, RA inhibits HeLa proliferation and induces apoptosis and autophagy via suppressing HPV18E6/E7, PD-L1 and VDR, and VD3 showed reinforced effects of RA on HeLa cells. Therefore, combined usage of VD3 with RA might be a potential novel immunotherapy strategy for HPV-related diseases.
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Affiliation(s)
- Zhiyu Li
- Department of Dermatology, Drum Tower School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Biyun Xu
- Department of Statistics, Drum Tower School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuexin Sun
- Department of Dermatology, Drum Tower School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lanbo Zhou
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yue Tao
- Department of Dermatology, Drum Tower School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wenjun Hou
- Department of Dermatology, Drum Tower School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jun Bao
- Department of Dermatology, Drum Tower School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jun Liu
- Department of Dermatology, Drum Tower School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Weixin Fan
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Wilczyński JR. Cancer Stem Cells: An Ever-Hiding Foe. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:219-251. [PMID: 35165866 DOI: 10.1007/978-3-030-91311-3_8] [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: 06/14/2023]
Abstract
Cancer stem cells are a population of cells enable to reproduce the original phenotype of the tumor and capable to self-renewal, which is crucial for tumor proliferation, differentiation, recurrence, and metastasis, as well as chemoresistance. Therefore, the cancer stem cells (CSCs) have become one of the main targets for anticancer therapy and many ongoing clinical trials test anti-CSCs efficacy of plenty of drugs. This chapter describes CSCs starting from general description of this cell population, through CSCs markers, signaling pathways, genetic and epigenetic regulation, role of epithelial-mesenchymal transition (EMT) transition and autophagy, cooperation with microenvironment (CSCs niche), and finally role of CSCs in escaping host immunosurveillance against cancer.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecologic Surgery and Gynecologic Oncology, Medical University of Lodz, Lodz, Poland.
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18
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Abd El-Aziz YS, Leck LYW, Jansson PJ, Sahni S. Emerging Role of Autophagy in the Development and Progression of Oral Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:6152. [PMID: 34944772 PMCID: PMC8699656 DOI: 10.3390/cancers13246152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/13/2022] Open
Abstract
Autophagy is a cellular catabolic process, which is characterized by degradation of damaged proteins and organelles needed to supply the cell with essential nutrients. At basal levels, autophagy is important to maintain cellular homeostasis and development. It is also a stress responsive process that allows the cells to survive when subjected to stressful conditions such as nutrient deprivation. Autophagy has been implicated in many pathologies including cancer. It is well established that autophagy plays a dual role in different cancer types. There is emerging role of autophagy in oral squamous cell carcinoma (OSCC) development and progression. This review will focus on the role played by autophagy in relation to different aspects of cancer progression and discuss recent studies exploring the role of autophagy in OSCC. It will further discuss potential therapeutic approaches to target autophagy in OSCC.
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Affiliation(s)
- Yomna S. Abd El-Aziz
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta 31527, Egypt
| | - Lionel Y. W. Leck
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Patric J. Jansson
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Sumit Sahni
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
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Abd El-Aziz YS, Gillson J, Jansson PJ, Sahni S. Autophagy: A promising target for triple negative breast cancers. Pharmacol Res 2021; 175:106006. [PMID: 34843961 DOI: 10.1016/j.phrs.2021.106006] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/16/2021] [Accepted: 11/23/2021] [Indexed: 01/18/2023]
Abstract
Triple negative breast cancer (TNBC) is the most aggressive type of breast cancers which constitutes about 15% of all breast cancer cases and characterized by negative expression of hormonal receptors and human epidermal growth factor receptor 2 (HER2). Thus, endocrine and HER2 targeted therapies are not effective toward TNBCs, and they mainly rely on chemotherapy and surgery for treatment. Despite recent advances in chemotherapy, 40% of TNBC patients develop a metastatic relapse and recurrence. Therefore, understanding the molecular profile of TNBC is warranted to identify targets that can be selected for the development of a new and effective therapeutic approach. Autophagy is an internal defensive mechanism that allows the cells to survive under different stressors. It has been well known that autophagy exerts a crucial role in cancer progression. The critical role of autophagy in TNBC progression is emerging in recent years. This review will discuss autophagic pathway, how autophagy affects TNBC progression and recent therapeutic approaches that can target autophagy as a new treatment modality.
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Affiliation(s)
- Yomna S Abd El-Aziz
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Kolling Institute of Medical Research, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Josef Gillson
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Kolling Institute of Medical Research, St Leonards, NSW, Australia
| | - Patric J Jansson
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Kolling Institute of Medical Research, St Leonards, NSW, Australia; Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Sumit Sahni
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Kolling Institute of Medical Research, St Leonards, NSW, Australia.
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20
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Apilan AG, Mothersill C. Targeted and Non-Targeted Mechanisms for Killing Hypoxic Tumour Cells-Are There New Avenues for Treatment? Int J Mol Sci 2021; 22:8651. [PMID: 34445354 PMCID: PMC8395506 DOI: 10.3390/ijms22168651] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/07/2021] [Accepted: 08/09/2021] [Indexed: 11/25/2022] Open
Abstract
PURPOSE A major issue in radiotherapy is the relative resistance of hypoxic cells to radiation. Historic approaches to this problem include the use of oxygen mimetic compounds to sensitize tumour cells, which were unsuccessful. This review looks at modern approaches aimed at increasing the efficacy of targeting and radiosensitizing hypoxic tumour microenvironments relative to normal tissues and asks the question of whether non-targeted effects in radiobiology may provide a new "target". Novel techniques involve the integration of recent technological advancements such as nanotechnology, cell manipulation, and medical imaging. Particularly, the major areas of research discussed in this review include tumour hypoxia imaging through PET imaging to guide carbogen breathing, gold nanoparticles, macrophage-mediated drug delivery systems used for hypoxia-activate prodrugs, and autophagy inhibitors. Furthermore, this review outlines several features of these methods, including the mechanisms of action to induce radiosensitization, the increased accuracy in targeting hypoxic tumour microenvironments relative to normal tissue, preclinical/clinical trials, and future considerations. CONCLUSIONS This review suggests that the four novel tumour hypoxia therapeutics demonstrate compelling evidence that these techniques can serve as powerful tools to increase targeting efficacy and radiosensitizing hypoxic tumour microenvironments relative to normal tissue. Each technique uses a different way to manipulate the therapeutic ratio, which we have labelled "oxygenate, target, use, and digest". In addition, by focusing on emerging non-targeted and out-of-field effects, new umbrella targets are identified, which instead of sensitizing hypoxic cells, seek to reduce the radiosensitivity of normal tissues.
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21
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Lin YX, Wang Y, Ding J, Jiang A, Wang J, Yu M, Blake S, Liu S, Bieberich CJ, Farokhzad OC, Mei L, Wang H, Shi J. Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models. Sci Transl Med 2021; 13:13/599/eaba9772. [PMID: 34162754 DOI: 10.1126/scitranslmed.aba9772] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 12/29/2020] [Accepted: 05/17/2021] [Indexed: 12/12/2022]
Abstract
Increasing clinical evidence has demonstrated that the deletion or mutation of tumor suppressor genes such as the gene-encoding phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in cancer cells may correlate with an immunosuppressive tumor microenvironment (TME) and poor response or resistance to immune checkpoint blockade (ICB) therapy. It is largely unknown whether the restoration of functional PTEN may modulate the TME and improve the tumor's sensitivity to ICB therapy. Here, we demonstrate that mRNA delivery by polymeric nanoparticles can effectively induce expression of PTEN in Pten-mutated melanoma cells and Pten-null prostate cancer cells, which in turn induces autophagy and triggers cell death-associated immune activation via release of damage-associated molecular patterns. In vivo results illustrated that PTEN mRNA nanoparticles can reverse the immunosuppressive TME by promoting CD8+ T cell infiltration of the tumor tissue, enhancing the expression of proinflammatory cytokines, such as interleukin-12, tumor necrosis factor-α, and interferon-γ, and reducing regulatory T cells and myeloid-derived suppressor cells. The combination of PTEN mRNA nanoparticles with an immune checkpoint inhibitor, anti-programmed death-1 antibody, results in a highly potent antitumor effect in a subcutaneous model of Pten-mutated melanoma and an orthotopic model of Pten-null prostate cancer. Moreover, the combinatorial treatment elicits immunological memory in the Pten-null prostate cancer model.
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Affiliation(s)
- Yao-Xin Lin
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yi Wang
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,CAS Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing 100190, China.,Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianxun Ding
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Aiping Jiang
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jie Wang
- CAS Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing 100190, China.,Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mian Yu
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
| | - Sara Blake
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
| | - Shuaishuai Liu
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250 USA
| | - Charles J Bieberich
- Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250 USA.,University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Omid C Farokhzad
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | - Lin Mei
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Guangzhou, Guangdong 510006, China. .,Tianjin Key Laboratory of Biomedical Materials and Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Hao Wang
- CAS Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing 100190, China. .,Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jinjun Shi
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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22
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Jiang T, Chen X, Ren X, Yang JM, Cheng Y. Emerging role of autophagy in anti-tumor immunity: Implications for the modulation of immunotherapy resistance. Drug Resist Updat 2021; 56:100752. [PMID: 33765484 DOI: 10.1016/j.drup.2021.100752] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 01/29/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023]
Abstract
Immunotherapies such as CAR-T cell transfer and antibody-targeted therapy have produced promising clinical outcomes in patients with advanced and metastatic cancer that are resistant to conventional therapies. However, with increasing use of cancer immunotherapy in clinical treatment, multiple therapy-resistance mechanisms have gradually emerged. The tumor microenvironment (TME), an integral component of cancer, can significantly influence the therapeutic response. Thus, it is worth exploring the potential of TME in modulating therapy resistance, in the hope to devise novel strategies to reinforcing anti-cancer treatments such as immunotherapy. As a crucial recycling process in the complex TME, the role of autophagy in tumor immunity has been increasingly appreciated. Firstly, autophagy in tumor cells can affect their immune response through modulating MHC-I-antigen complexes, thus modulating immunogenic tumor cell death, changing functions of immune cells via secretory autophagy, reducing the NK- and CTL-mediated cell lysis and degradation of immune checkpoint proteins. Secondly, autophagy is critical for the differentiation, maturation and survival of immune cells in the TME and can significantly affect the immune function of these cells, thereby regulating the anti-tumor immune response. Thirdly, alteration of autophagic activity in stromal cells, especially in fibroblasts, can reconstruct the three-dimensional stromal environment and metabolic reprogramming in the TME. A number of studies have demonstrated that optimal induction or inhibition of autophagy may lead to effective therapeutic regimens when combined with immunotherapy. This review discusses the important roles of autophagy in tumor cells, immune cells and stromal cells in the context of tumor immunity, and the potential of combining the autophagy-based therapy with immunotherapy as novel therapeutic approaches against cancer.
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Affiliation(s)
- Ting Jiang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Xisha Chen
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Xingcong Ren
- Department of Toxicology and Cancer Biology, Department of Pharmacology, and Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA
| | - Jin-Ming Yang
- Department of Toxicology and Cancer Biology, Department of Pharmacology, and Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA.
| | - Yan Cheng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
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23
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Zhou W, Wang H, Yang Y, Chen ZS, Zou C, Zhang J. Chloroquine against malaria, cancers and viral diseases. Drug Discov Today 2020; 25:2012-2022. [PMID: 32947043 PMCID: PMC7492153 DOI: 10.1016/j.drudis.2020.09.010] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/13/2020] [Accepted: 09/10/2020] [Indexed: 02/08/2023]
Abstract
Quinoline (QN) derivatives are often used for the prophylaxis and treatment of malaria. Chloroquine (CQ), a protonated, weakly basic drug, exerts its antimalarial effect mainly by increasing pH and accumulating in the food vacuole of the parasites. Repurposing CQ is an emerging strategy for new indications. Given the inhibition of autophagy and its immunomodulatory action, CQ shows positive efficacy against cancer and viral diseases, including Coronavirus 2019 (COVID-19). Here, we review the underlying mechanisms behind the antimalarial, anticancer and antiviral effects of CQ. We also discuss the clinical evidence for the use of CQ and hydroxychloroquine (HCQ) against COVID-19.
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Affiliation(s)
- Wenmin Zhou
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, PR China
| | - Hui Wang
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, PR China; Guangzhou Institute of Pediatrics/Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, PR China; The First Affiliated Hospital, Hainan Medical University, Haikou, 571199, PR China
| | - Yuqi Yang
- College of Pharmacy and Health Sciences, St John's University, Queens, New York, NY 11439, USA
| | - Zhe-Sheng Chen
- College of Pharmacy and Health Sciences, St John's University, Queens, New York, NY 11439, USA.
| | - Chang Zou
- The Second Clinical Medical College of Jinan University, Shenzhen, 518020, PR China.
| | - Jianye Zhang
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, PR China; Guangzhou Institute of Pediatrics/Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, PR China; The First Affiliated Hospital, Hainan Medical University, Haikou, 571199, PR China.
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24
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Vadlakonda L, Indracanti M, Kalangi SK, Gayatri BM, Naidu NG, Reddy ABM. The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer. J Diabetes Metab Disord 2020; 19:1731-1775. [PMID: 33520860 DOI: 10.1007/s40200-020-00566-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
Purpose Re-examine the current metabolic models. Methods Review of literature and gene networks. Results Insulin activates Pi uptake, glutamine metabolism to stabilise lipid membranes. Tissue turnover maintains the metabolic health. Current model of intermediary metabolism (IM) suggests glucose is the source of energy, and anaplerotic entry of fatty acids and amino acids into mitochondria increases the oxidative capacity of the TCA cycle to produce the energy (ATP). The reduced cofactors, NADH and FADH2, have different roles in regulating the oxidation of nutrients, membrane potentials and biosynthesis. Trans-hydrogenation of NADH to NADPH activates the biosynthesis. FADH2 sustains the membrane potential during the cell transformations. Glycolytic enzymes assume the non-canonical moonlighting functions, enter the nucleus to remodel the genetic programmes to affect the tissue turnover for efficient use of nutrients. Glycosylation of the CD98 (4F2HC) stabilises the nutrient transporters and regulates the entry of cysteine, glutamine and BCAA into the cells. A reciprocal relationship between the leucine and glutamine entry into cells regulates the cholesterol and fatty acid synthesis and homeostasis in cells. Insulin promotes the Pi transport from the blood to tissues, activates the mitochondrial respiratory activity, and glutamine metabolism, which activates the synthesis of cholesterol and the de novo fatty acids for reorganising and stabilising the lipid membranes for nutrient transport and signal transduction in response to fluctuations in the microenvironmental cues. Fatty acids provide the lipid metabolites, activate the second messengers and protein kinases. Insulin resistance suppresses the lipid raft formation and the mitotic slippage activates the fibrosis and slow death pathways.
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Affiliation(s)
| | - Meera Indracanti
- Institute of Biotechnology, University of Gondar, Gondar, Ethiopia
| | - Suresh K Kalangi
- Amity Stem Cell Institute, Amity University Haryana, Amity Education Valley Pachgaon, Manesar, Gurugram, HR 122413 India
| | - B Meher Gayatri
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
| | - Navya G Naidu
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
| | - Aramati B M Reddy
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046 India
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25
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Horton RH, Wileman T, Rushworth SA. Autophagy Driven Extracellular Vesicles in the Leukaemic Microenvironment. Curr Cancer Drug Targets 2020; 20:501-512. [PMID: 32342819 DOI: 10.2174/1568009620666200428111051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 12/27/2019] [Accepted: 03/29/2020] [Indexed: 12/12/2022]
Abstract
The leukaemias are a heterogeneous group of blood cancers, which together, caused 310,000 deaths in 2016. Despite significant research into their biology and therapeutics, leukaemia is predicted to account for an increased 470,000 deaths in 2040. Many subtypes remain without targeted therapy, and therefore the mainstay of treatment remains generic cytotoxic drugs with bone marrow transplant the sole definitive option. In this review, we will focus on cellular mechanisms which have the potential for therapeutic exploitation to specifically target and treat this devastating disease. We will bring together the disciplines of autophagy and extracellular vesicles, exploring how the dysregulation of these mechanisms can lead to changes in the leukaemic microenvironment and the subsequent propagation of disease. The dual effect of these mechanisms in the disease microenvironment is not limited to leukaemia; therefore, we briefly explore their role in autoimmunity, inflammation and degenerative disease.
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Affiliation(s)
- Rebecca H Horton
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7UQ, United Kingdom
| | - Tom Wileman
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7UQ, United Kingdom
| | - Stuart A Rushworth
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7UQ, United Kingdom
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26
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Zhang Y, Pan N, Sheng Y, Zhou M, Wen Z, Chen Y, Huang F, Wang LX. Hypoxia enhances IL-10-producing B cell generation through upregulating high-mobility group B1 on tumor cell-released autophagosomes. Immunol Lett 2019; 216:36-42. [PMID: 31568811 DOI: 10.1016/j.imlet.2019.09.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 09/12/2019] [Accepted: 09/26/2019] [Indexed: 01/28/2023]
Abstract
As common features of human solid tumors, hypoxia and nutrient starvation play multifaceted roles in cancer progress. However, the mechanisms are far from clear. Our previous work has indicated that tumor cell-released autophagosomes (TRAPs) are sufficient to suppress anti-tumor immune response in mouse by inducing IL-10-producing B cells through high-mobility group B1 (HMGB1). Here, we hypothesized that hypoxia or starvation might exert immunosuppressive effect through upregulating HMGB1 on TRAPs. We found that HMGB1 on TRAPs from human hepatocellular carcinoma cell line HepG2 played a significant role in IL-10-producing B cell induction. HMGB1 in tumor cells was upregulated under hypoxia and starvation, but only hypoxia significantly enhanced the level of HMGB1 present on the surfaces of TRAPs. Moreover, hypoxic TRAPs induced more IL-10-producing B cells with suppressive activities on CD4+ and CD8+ T cells. The finding indicates the role of TRAPs as a messenger of hypoxic response to enhance immunosuppression in tumor microenvironment.
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Affiliation(s)
- Yue Zhang
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing, Jiangsu Province, 210009, China
| | - Ning Pan
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing, Jiangsu Province, 210009, China.
| | - Yemeng Sheng
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing, Jiangsu Province, 210009, China; Health Science Center, Xizang Minzu University, No. 6 Wenhui Donglu, Xianyang, Shanxi Province, 712082, China
| | - Meng Zhou
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing, Jiangsu Province, 210009, China
| | - Zhifa Wen
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing, Jiangsu Province, 210009, China
| | - Yongqiang Chen
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing, Jiangsu Province, 210009, China
| | - Fang Huang
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing, Jiangsu Province, 210009, China; Health Science Center, Xizang Minzu University, No. 6 Wenhui Donglu, Xianyang, Shanxi Province, 712082, China
| | - Li-Xin Wang
- Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Rd., Nanjing, Jiangsu Province, 210009, China; Health Science Center, Xizang Minzu University, No. 6 Wenhui Donglu, Xianyang, Shanxi Province, 712082, China.
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27
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Udristioiu A, Nica-Badea D. Autophagy dysfunctions associated with cancer cells and their therapeutic implications. Biomed Pharmacother 2019; 115:108892. [PMID: 31029889 DOI: 10.1016/j.biopha.2019.108892] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/12/2019] [Accepted: 04/17/2019] [Indexed: 02/08/2023] Open
Abstract
Genomic analysis of human cancers indicates that the loss or mutation of core autophagy related genes, (ATG) is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Several studies have demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles in cells: a cellular process that maintains the homeostasis of the normal cell, while self-defects can lead to a lawsuit to accelerate tumorigenesis and developing diseases, such as cancer. Depending on different contexts, autophagy dysfunctions may play a role: neutral, tumor-suppressive, or tumor-promoting. The process of autophagy may function in tumor suppression by mitigating metabolic stress and, in concert with apoptosis, by preventing tumor cell death by necrosis. In this case, optimal combination of autophagy inhibition (CQ, HCQ) with other conventional therapies - chemo or radiotherapy in a variety of tumor types in different phases can be successful approaches for improve the effect of anticancer therapies. This review examines recent insights of the molecular mechanism of autophagy and the potential roles of autophagy in cell death, cancer development, overview of the most recent therapeutic strategies involving autophagy modulators in cancer prevention and therapeutic opportunities.
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Affiliation(s)
- Aurelian Udristioiu
- Molecular Biology, Medicine Faculty, Titu Maiorescu University, Bucharest, Romania
| | - Delia Nica-Badea
- Medicinal and Behavioral Sciences Faculty, Constantin Brâncuși University, Târgu - Jiu, Romania.
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28
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Chen Q, Men Y, Wang H, Chen R, Han X, Liu J. Curcumin Inhibits Proliferation and Migration of A549 Lung Cancer Cells Through Activation of ERK1/2 Pathway-induced Autophagy. Nat Prod Commun 2019. [DOI: 10.1177/1934578x19848179] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Affiliation(s)
- Quangang Chen
- Laboratory Animal Center, Xuzhou Medical University, Jiangsu, China
| | - Yanjuan Men
- Laboratory Animal Center, Xuzhou Medical University, Jiangsu, China
| | - Hui Wang
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Renjin Chen
- Laboratory Animal Center, Xuzhou Medical University, Jiangsu, China
| | - Xufeng Han
- Laboratory Animal Center, Xuzhou Medical University, Jiangsu, China
| | - Jing Liu
- Department of Respiratory Medicine, Xuzhou Central Hospital, Affiliated Xuzhou Hospital of Medical College of Southeast University, Jiangsu, China
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29
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Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells. Sci Rep 2019; 9:5637. [PMID: 30948782 PMCID: PMC6449403 DOI: 10.1038/s41598-019-42220-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 03/26/2019] [Indexed: 01/03/2023] Open
Abstract
Eliminating mutant p53 (mt p53) protein could be a useful strategy to treat mt p53 tumors and potentially improve the prognosis of cancer patients. In this study, we unveil different mechanisms that eliminate p53-R248Q, one of the most frequent mutants found in human cancers. We show that the Hsp90 inhibitor 17-AAG eliminates R248Q by stimulating macroautophagy under normal growth conditions. Metabolic stress induced by the pyruvate dehydrogenase kinase-1 (PDK1) inhibitor dichloroacetate (DCA) inhibits the macroautophagy pathway. This induces the accumulation of R248Q, which in addition further inhibits macroautophagy. Combination of DCA and 17-AAG further decreases the autophagy flux compared to DCA alone. Despite this, this co-treatment strongly decreases R248Q levels. In this situation of metabolic stress, 17-AAG induces the binding of p53-R248Q to Hsc70 and the activation of Chaperone-Mediated Autophagy (CMA), leading to higher R248Q degradation than in non-stress conditions. Thus, different metabolic contexts induce diverse autophagy mechanisms that degrade p53-R248Q, and under metabolic stress, its degradation is CMA-mediated. Hence, we present different strategies to eliminate this mutant and provide new evidence of the crosstalk between macroautophagy and CMA and their potential use to target mutant p53.
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30
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Autophagy in regulatory T cells: A double-edged sword in disease settings. Mol Immunol 2019; 109:43-50. [PMID: 30852245 DOI: 10.1016/j.molimm.2019.02.004] [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: 10/10/2018] [Revised: 01/03/2019] [Accepted: 02/05/2019] [Indexed: 12/21/2022]
Abstract
Autophagy is an evolutionarily conserved catabolic process that directs cytoplasmic proteins, organelles and microbes to lysosomes for degradation. It not only represents an essential cell-intrinsic mechanism to protect against internal and external stresses but also shapes both innate and adaptive immunity. Regulatory T cells (Tregs) are a developmentally and functionally distinct T cell subpopulation engaged in sustaining immunological self-tolerance and homeostasis. There is compelling evidence that autophagy is actively regulated in Tregs and serves as a central signal-dependent controller for Tregs by restraining excessive apoptotic and metabolic activities. In this review, we discuss how autophagy modulates the stability and functionality of Tregs in different disease settings, and provide a perspective on how manipulation of autophagy enables better control of immune response by targeting the generation of Tregs and the maintenance of their stability.
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31
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Nazio F, Bordi M, Cianfanelli V, Locatelli F, Cecconi F. Autophagy and cancer stem cells: molecular mechanisms and therapeutic applications. Cell Death Differ 2019; 26:690-702. [PMID: 30728463 PMCID: PMC6460398 DOI: 10.1038/s41418-019-0292-y] [Citation(s) in RCA: 287] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 01/15/2019] [Accepted: 01/16/2019] [Indexed: 02/07/2023] Open
Abstract
Autophagy and mitophagy act in cancer as bimodal processes, whose differential functions strictly depend on cancer ontogenesis, progression, and type. For instance, they can act to promote cancer progression by helping cancer cells survive stress or, instead, when mutated or abnormal, to induce carcinogenesis by influencing cell signaling or promoting intracellular toxicity. For this reason, the study of autophagy in cancer is the main focus of many researchers and several clinical trials are already ongoing to manipulate autophagy and by this way determine the outcome of disease therapy. Since the establishment of the cancer stem cell (CSC) theory and the discovery of CSCs in individual cancer types, autophagy and mitophagy have been proposed as key mechanisms in their homeostasis, dismissal or spread, even though we still miss a comprehensive view of how and by which regulatory molecules these two processes drive cell fate. In this review, we will dive into the deep water of autophagy, mitophagy, and CSCs and offer novel viewpoints on possible therapeutic strategies, based on the modulation of these degradative systems.
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Affiliation(s)
- Francesca Nazio
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy
| | - Matteo Bordi
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy
- Department of Biology, University of Tor Vergata, 00133, Rome, Italy
| | - Valentina Cianfanelli
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, 2100, Copenhagen, Denmark
| | - Franco Locatelli
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy
- Department of Gynecology/Obstetrics and Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Francesco Cecconi
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy.
- Department of Biology, University of Tor Vergata, 00133, Rome, Italy.
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, 2100, Copenhagen, Denmark.
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Jiang GM, Tan Y, Wang H, Peng L, Chen HT, Meng XJ, Li LL, Liu Y, Li WF, Shan H. The relationship between autophagy and the immune system and its applications for tumor immunotherapy. Mol Cancer 2019; 18:17. [PMID: 30678689 PMCID: PMC6345046 DOI: 10.1186/s12943-019-0944-z] [Citation(s) in RCA: 261] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 01/14/2019] [Indexed: 12/15/2022] Open
Abstract
Autophagy is a genetically well-controlled cellular process that is tightly controlled by a set of core genes, including the family of autophagy-related genes (ATG). Autophagy is a “double-edged sword” in tumors. It can promote or suppress tumor development, which depends on the cell and tissue types and the stages of tumor. At present, tumor immunotherapy is a promising treatment strategy against tumors. Recent studies have shown that autophagy significantly controls immune responses by modulating the functions of immune cells and the production of cytokines. Conversely, some cytokines and immune cells have a great effect on the function of autophagy. Therapies aiming at autophagy to enhance the immune responses and anti-tumor effects of immunotherapy have become the prospective strategy, with enhanced antigen presentation and higher sensitivity to CTLs. However, the induction of autophagy may also benefit tumor cells escape from immune surveillance and result in intrinsic resistance against anti-tumor immunotherapy. Increasing studies have proven the optimal use of either ATG inducers or inhibitors can restrain tumor growth and progression by enhancing anti-tumor immune responses and overcoming the anti-tumor immune resistance in combination with several immunotherapeutic strategies, indicating that induction or inhibition of autophagy might show us a prospective therapeutic strategy when combined with immunotherapy. In this article, the possible mechanisms of autophagy regulating immune system, and the potential applications of autophagy in tumor immunotherapy will be discussed.
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Affiliation(s)
- Guan-Min Jiang
- Department of Clinical laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China. .,Central Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
| | - Yuan Tan
- Department of Clinical Laboratory, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Hao Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, China
| | - Liang Peng
- Department of Clinical laboratory, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Hong-Tao Chen
- Department of Clinical laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Xiao-Jun Meng
- Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Ling-Ling Li
- Central Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Yan Liu
- Department of Clinical laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Wen-Fang Li
- Department of Clinical laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Hong Shan
- Key Laboratory of Biomedical Imaging of Guangdong Province, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
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Wierz M, Pierson S, Gargiulo E, Guerin C, Moussay E, Paggetti J. Purification of Leukemia-Derived Exosomes to Study Microenvironment Modulation. Methods Mol Biol 2019; 1884:231-245. [PMID: 30465207 DOI: 10.1007/978-1-4939-8885-3_16] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Exosomes are membrane-enclosed vesicles released by different cell types into the extracellular space. As mediators of intercellular communication, they are involved in multiple physiological processes, but they are also associated with the pathogenesis of human malignancies including leukemia. Isolation of exosomes enables the characterization of their role in microenvironment modulation as well as their participation in disease pathology. A variety of strategies and techniques exists to purify exosomes from many biological fluids (e.g., blood, urine, and saliva). Here, we describe the efficient production of large quantities of exosomes from leukemic cell lines by using CELLine bioreactors based on two-compartment technology, as well as their isolation and purification by combining differential centrifugation and ultracentrifugation through a density gradient (17% OptiPrep™ cushion). Thus, exosomes are appropriately prepared for characterization by western blotting to detect exosome markers or imaging flow cytometry (ImageStream), and for downstream analyses such as the internalization in microenvironmental cells by confocal imaging or flow cytometry, methods which are also described in this chapter.
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Affiliation(s)
- Marina Wierz
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Sandrine Pierson
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Ernesto Gargiulo
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Coralie Guerin
- National Cytometry Platform, Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Etienne Moussay
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Jerome Paggetti
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
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Autophagy and Its Role in Protein Secretion: Implications for Cancer Therapy. Mediators Inflamm 2018; 2018:4231591. [PMID: 30622432 PMCID: PMC6304875 DOI: 10.1155/2018/4231591] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/26/2018] [Accepted: 10/02/2018] [Indexed: 12/11/2022] Open
Abstract
Autophagy is a protein and organelle degradation pathway important for the maintenance of cytoplasmic homeostasis and for providing nutrients for survival in response to stress conditions. Recently, autophagy has been shown to be important for the secretion of diverse proteins involved in inflammation, intercellular signaling, and cancer progression. The role of autophagy in cancer depends on the stage of tumorigenesis, serving a tumor-suppressor role before transformation and a tumor-survival function once a tumor is established. We review recent evidence demonstrating the complexity of autophagy regulation during cancer, considering the interaction of autophagy with protein secretion pathways. Autophagy manipulation during cancer treatment is likely to affect protein secretion andinter-cellular signaling either to the neighboring cancer cells or to the antitumoral immune response. This will be an important consideration during cancer therapy since several clinical trials are trying to manipulate autophagy in combination with chemotherapy for the treatment of diverse types of cancers.
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Yewdall NA, Mason AF, van Hest JCM. The hallmarks of living systems: towards creating artificial cells. Interface Focus 2018; 8:20180023. [PMID: 30443324 PMCID: PMC6227776 DOI: 10.1098/rsfs.2018.0023] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2018] [Indexed: 01/01/2023] Open
Abstract
Despite the astonishing diversity and complexity of living systems, they all share five common hallmarks: compartmentalization, growth and division, information processing, energy transduction and adaptability. In this review, we give not only examples of how cells satisfy these requirements for life and the ways in which it is possible to emulate these characteristics in engineered platforms, but also the gaps that remain to be bridged. The bottom-up synthesis of life-like systems continues to be driven forward by the advent of new technologies, by the discovery of biological phenomena through their transplantation to experimentally simpler constructs and by providing insights into one of the oldest questions posed by mankind, the origin of life on Earth.
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Affiliation(s)
| | | | - Jan C. M. van Hest
- Eindhoven University of Technology, PO Box 513 (STO 3.31), Eindhoven, MB, The Netherlands
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El-Abd E, El-Sheikh M, Zaky S, Fayed W, El-Zoghby S. Plasma TuM2-PK correlates with tumor size, CRP and CA 15-3 in metastatic breast carcinomas; short versus long term follow up study of the Egyptian breast cancer patients. Cancer Biomark 2018; 20:123-133. [PMID: 28869444 DOI: 10.3233/cbm-160482] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND The key regulator of tumor metabolome is the glycolytic isoenzyme M2-PK which favors the generation of nucleic acid via glutaminolysis as hypoxic adaptive mechanism in the tumor cells. AIM The study aimed to evaluate the prognostic role of M2-PK, CRP, and CA 15-3 in preoperative and metastatic breast carcinomas. PATIENTS AND METHODS The study included 70 females; 15 controls, 33 preoperative primary breast carcinomas clinically metastasis free, and 22 clinically diagnosed metastatic breast carcinomas. M2-PK and CA 15-3 were detected by ELISA. CRP was quantified using the CRP LATEX kit. RESULTS TuM2-PK significantly increased in metastatic and preoperative groups when compared to controls (p= 0.049, p= 0.001); respectively. Both CRP and CA 15-3 were significantly increased in metastatic than the preoperative group (p= 0.002). CA 15-3 was significantly increased in both groups when compared to controls (p= 0.016; p< 0.001; respectively). TuM2-PK level significantly related to tumor size in metastatic group (p= 0.006) and with menstruation status (p= 0.039), and liver metastasis (p= 0.036) in preoperative group. TuM2-PK significantly correlated with CRP (r= 0.793, p= 0.004), and CA 15-3 (r= 0.568, p= 0.006) in the metastatic group.Metastatic group with TuM2-PK ⩽ 15 U/ml had significantly higher survival rate than those with > 15 U/ml (χ2= 13.841, p< 0.001) within 3.3-4.2 but not after 10-20 years follow up period. Metastasis to bone and lymph nodes significantly increased in the metastatic than the preoperative group (p= 0.002, p= 0.013; respectively). Within 3.3-4.2 years, CA15.3 has the highest prognostic performance in metastatic group while both TuM2-PK and CRP have same specificity. On the other hand, TuM2-PK has the highest prognostic performance in preoperative group. After 20 years follow up period, there was neither significant difference in the performance of the three markers in predicting mortality in metastatic and preoperative groups nor in predicting metastasis in preoperative group. CONCLUSION Current results document for the first time, a cross-talk between TuM2-PK and each of CRP and CA 15-3 in metastatic breast cancer.
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Affiliation(s)
- Eman El-Abd
- Radiation Sciences Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.,Molecular Biology Department, Medical Technology Centre, MRI, Alexandria University, Alexandria, Egypt
| | - Marwa El-Sheikh
- Medical Applied Chemistry, MRI, Alexandria University, Alexandria, Egypt
| | - Sameh Zaky
- Cancer Management and Research, MRI, Alexandria University, Alexandria, Egypt
| | - Wagdy Fayed
- Experimental and Clinical Surgery, MRI, Alexandria University, Alexandria, Egypt
| | - Safinaz El-Zoghby
- Medical Applied Chemistry, MRI, Alexandria University, Alexandria, Egypt
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Janji B, Berchem G, Chouaib S. Targeting Autophagy in the Tumor Microenvironment: New Challenges and Opportunities for Regulating Tumor Immunity. Front Immunol 2018; 9:887. [PMID: 29922284 PMCID: PMC5996896 DOI: 10.3389/fimmu.2018.00887] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 04/10/2018] [Indexed: 12/19/2022] Open
Abstract
Cancer cells evolve in the tumor microenvironment, which is now well established as an integral part of the tumor and a determinant player in cancer cell adaptation and resistance to anti-cancer therapies. Despite the remarkable and fairly rapid progress over the past two decades regarding our understanding of the role of the tumor microenvironment in cancer development, its precise contribution to cancer resistance is still fragmented. This is mainly related to the complexity of the “tumor ecosystem” and the diversity of the stromal cell types that constitute the tumor microenvironment. Emerging data indicate that several factors, such as hypoxic stress, activate a plethora of resistance mechanisms, including autophagy, in tumor cells. Hypoxia-induced autophagy in the tumor microenvironment also activates several tumor escape mechanisms, which effectively counteract anti-tumor immune responses mediated by natural killer and cytotoxic T lymphocytes. Therefore, strategies aiming at targeting autophagy in cancer cells in combination with other therapeutic strategies have inspired significant interest to overcome immunological tolerance and promote tumor regression. However, a number of obstacles still hamper the application of autophagy inhibitors in clinics. First, the lack of selectivity of the current pharmacological inhibitors of autophagy makes difficult to draw a clear statement about its effective contribution in cancer. Second, autophagy has been also described as an important mechanism in tumor cells involved in presentation of antigens to T cells. Third, there is a circumstantial evidence that autophagy activation in some innate immune cells may support the maturation of these cells, and it is required for their anti-tumor activity. In this review, we will address these aspects and discuss our current knowledge on the benefits and the drawbacks of targeting autophagy in the context of anti-tumor immunity. We believe that it is important to resolve these issues to predict the use of autophagy inhibitors in combination with immunotherapies in clinical settings.
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Affiliation(s)
- Bassam Janji
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, Luxembourg
| | - Guy Berchem
- Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, Luxembourg.,Centre Hospitalier du Luxembourg, Department of Hemato-Oncology, Luxembourg City, Luxembourg
| | - Salem Chouaib
- INSERM U1186, Gustave Roussy Cancer Center, Villejuif, France.,Thumbay Research Institute for Precision Medicine - Gulf Medical University, Ajman, United Arab Emirates
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Li R, Zhou R, Zhang J. Function of PM2.5 in the pathogenesis of lung cancer and chronic airway inflammatory diseases. Oncol Lett 2018; 15:7506-7514. [PMID: 29725457 DOI: 10.3892/ol.2018.8355] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 02/28/2018] [Indexed: 12/14/2022] Open
Abstract
Previous research has identified that air pollution is associated with various respiratory diseases, but few studies have investigated the function served by particulate matter 2.5 (PM2.5) in these diseases. PM2.5 is known to cause epigenetic and microenvironmental alterations in lung cancer, including tumor-associated signaling pathway activation mediated by microRNA dysregulation, DNA methylation, and increased levels of cytokines and inflammatory cells. Autophagy and apoptosis of tumor cells may also be detected in lung cancer associated with PM2.5 exposure. A number of mechanisms are involved in triggering and aggravating asthma and COPD, including PM2.5-induced cytokine release and oxidative stress. The present review is an overview of the underlying molecular mechanisms of PM2.5-induced pathogenesis in lung cancer and chronic airway inflammatory diseases.
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Affiliation(s)
- Ruyi Li
- Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Rui Zhou
- Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Jiange Zhang
- Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
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Abstract
The proto-oncogene Myc is well known for its roles in promoting cell growth, proliferation and apoptosis. However, in this study, we found from a genetic screen that Myc inhibits, rather than promotes, cell death triggered by c-Jun N-terminal kinase (JNK) signaling in Drosophila. Firstly, expression of Drosophila Myc (dMyc) suppresses, whereas loss of dMyc enhances, ectopically activated JNK signaling-induced cell death. Secondly, dMyc impedes physiologically activated JNK pathway-mediated cell death. Thirdly, loss of dMyc triggers JNK pathway activation and JNK-dependent cell death. Finally, the mammalian cMyc gene, when expressed in Drosophila, impedes activated JNK signaling-induced cell death. Thus, besides its well-studied apoptosis promoting function, Myc also antagonizes JNK-mediated cell death in Drosophila, and this function is likely conserved from fly to human.
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Affiliation(s)
- Jiuhong Huang
- Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai, 200092, China
| | - Yu Feng
- Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai, 200092, China
| | - Xinhong Chen
- Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai, 200092, China
| | - Wenzhe Li
- Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai, 200092, China.
| | - Lei Xue
- Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai, 200092, China.
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Deregulation of Hexokinase II Is Associated with Glycolysis, Autophagy, and the Epithelial-Mesenchymal Transition in Tongue Squamous Cell Carcinoma under Hypoxia. BIOMED RESEARCH INTERNATIONAL 2018; 2018:8480762. [PMID: 29682563 PMCID: PMC5841093 DOI: 10.1155/2018/8480762] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/03/2018] [Accepted: 01/14/2018] [Indexed: 12/15/2022]
Abstract
The glycolytic enzyme Hexokinase (HKII) participates in tumor glycolysis and the progression of various cancers, but its clinicopathological effect on the progression of tongue squamous cell carcinoma (TSCC) and its role in glycolysis, autophagy, and the epithelial-mesenchymal transition of TSCC in a hypoxic microenvironment remain unknown. Our results showed that HKII expression was dramatically increased in TSCC tissues and that its upregulation was significantly associated with the presence of pathological differentiation, lymph node metastasis, and clinical stage. The level of autophagy-specific protein LC3, EMT-related proteins, and the migration and invasion capabilities of TSCC cells all increased under hypoxia. Moreover, hypoxia increased the glucose consumption and lactate production of TSCC cells, and we demonstrated that the expression of the glycolytic key gene HKII was significantly higher than in that of the control group. Notably, the downregulation of HKII resulted in a significant decrease of TSCC cell glucose consumption lactate production and autophagic activity during hypoxia. HKII knockdown blocked the migratory and invasive capacity of TSCC cells and we specifically determined that the EMT ability decreased. Therefore, our findings revealed that the upregulation of HKII enhanced glycolysis and increased autophagy and the epithelial-mesenchymal transition of tongue squamous cell carcinoma under hypoxia.
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Leu WJ, Swain SP, Chan SH, Hsu JL, Liu SP, Chan ML, Yu CC, Hsu LC, Chou YL, Chang WL, Hou DR, Guh JH. Non-immunosuppressive triazole-based small molecule induces anticancer activity against human hormone-refractory prostate cancers: the role in inhibition of PI3K/AKT/mTOR and c-Myc signaling pathways. Oncotarget 2018; 7:76995-77009. [PMID: 27769069 PMCID: PMC5363565 DOI: 10.18632/oncotarget.12765] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 10/14/2016] [Indexed: 12/14/2022] Open
Abstract
A series of triazole-based small molecules that mimic FTY720-mediated anticancer activity but minimize its immunosuppressive effect have been produced. SPS-7 is the most effective derivative displaying higher activity than FTY720 in anti-proliferation against human hormone-refractory prostate cancer (HRPC). It induced G1 arrest of cell cycle and subsequent apoptosis in thymidine block-mediated synchronization model. The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation. c-Myc overexpression replenished protein levels of cyclin D1 indicating that c-Myc was responsible for cell cycle regulation. PI3K/Akt/mTOR signaling pathways through p70S6K- and 4EBP1-mediated translational regulation are critical to cell proliferation and survival. SPS-7 significantly inhibited this translational pathway. Overexpression of Myr-Akt (constitutively active Akt) completely abolished SPS-7-induced inhibitory effect on mTOR/p70S6K/4EBP1 signaling and c-Myc protein expression, suggesting that PI3K/Akt serves as a key upstream regulator. SPS-7 also demonstrated substantial anti-tumor efficacy in an in vivo xenograft study using PC-3 mouse model. Notably, FTY720 but not SPS-7 induced a significant immunosuppressive effect as evidenced by depletion of marginal zone B cells, down-regulation of sphingosine-1-phosphate receptors and a decrease in peripheral blood lymphocytes. In conclusion, the data suggest that SPS-7 is not an immunosuppressant while induces anticancer effect against HRPC through inhibition of Akt/mTOR/p70S6K pathwaysthat down-regulate protein levels of both c-Myc and cyclin D1, leading to G1 arrest of cell cycle and subsequent apoptosis. The data also indicate the potential of SPS-7 since PI3K/Akt signalingis responsive for the genomic alterations in prostate cancer.
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Affiliation(s)
- Wohn-Jenn Leu
- School of Pharmacy, National Taiwan University, Taipei, Taiwan
| | | | - She-Hung Chan
- School of Pharmacy, National Taiwan University, Taipei, Taiwan
| | - Jui-Ling Hsu
- School of Pharmacy, National Taiwan University, Taipei, Taiwan
| | - Shih-Ping Liu
- Department of Urology, National Taiwan University Hospital, Taipei, Taiwan
| | - Mei-Ling Chan
- School of Pharmacy, National Taiwan University, Taipei, Taiwan
| | - Chia-Chun Yu
- School of Pharmacy, National Taiwan University, Taipei, Taiwan
| | - Lih-Ching Hsu
- School of Pharmacy, National Taiwan University, Taipei, Taiwan
| | - Yen-Lin Chou
- Department of Chemistry, National Central University, Jhong-li, Taoyuan, Taiwan
| | - Wei-Ling Chang
- School of Pharmacy, National Taiwan University, Taipei, Taiwan
| | - Duen-Ren Hou
- Department of Chemistry, National Central University, Jhong-li, Taoyuan, Taiwan
| | - Jih-Hwa Guh
- School of Pharmacy, National Taiwan University, Taipei, Taiwan
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Castellanos-Esparza YC, Wu S, Huang L, Buquet C, Shen R, Sanchez-Gonzalez B, García Latorre EA, Boyer O, Varin R, Jiménez-Zamudio LA, Janin A, Vannier JP, Li H, Lu H. Synergistic promoting effects of pentoxifylline and simvastatin on the apoptosis of triple-negative MDA-MB-231 breast cancer cells. Int J Oncol 2018; 52:1246-1254. [PMID: 29436616 DOI: 10.3892/ijo.2018.4272] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 11/14/2017] [Indexed: 11/06/2022] Open
Abstract
Pentoxifylline (PTX), a xanthine family molecule and simvastatin (SIM), an anti-hypercholesterolemic agent, have recently been considered as sensitizers to chemotherapy and radiotherapy. The present in vitro study evaluated their antitumor synergistic effects on MDA‑MB‑231 breast cancer cells characterized by the triple‑negative phenotype (TNP). The anti-proliferative effects of these two agents were evaluated by MTT and clonogenic assays. Cell cycle progression was examined using propidium iodide staining. Apoptosis was investigated by Annexin V labeling, and by examining caspase 3 activity and DNA fragmentation. Autophagic vesicles and reactive oxygen species (ROS) levels were monitored by flow cytometry. Western blot analysis was performed to evaluate molecular targets. Our results revealed that when used alone, PTX and SIM exerted antitumor effects. Nevertheless, used in combination, the inhibition of cell proliferation was synergistically superior (80% vs 42%) than that observed following treatment with each agent alone after 48 h. PTX alone (0.5 mM) induced both apoptosis (25%) and autophagy (25%); however, when used in combination with SIM (0.5 µM), the balance between these processes was disrupted and the cells underwent apoptosis (>65%) as opposed to autophagy (<13%). This imbalance was associated with an increase in ERK1/2 and AKT activation, but not with an increase in mTOR phosphorylation, and with the suppression of the NF-κB pathway. In addition, in the cells treated with both agents, almost 78% of the cells were arrested at the G0/G1 phase and lost their colony-forming ability (38±5%) compared to the cells treated with PTX alone (115±5%). On the whole, these results suggest that the induction of autophagy may be a protective mechanism preventing MDA‑MB‑231 cancer cell death. The combined use of PTX and SIM may drive dormant autophagic cancer cells to undergo apoptosis and thus this may be a novel treatment strategy for breast cancer characterized by the TNP.
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Affiliation(s)
- Yessica Cristina Castellanos-Esparza
- National Institute of Health and Medical Research, Medical Research Unit S-1165/Paris Diderot University, University Institute of Hematology, Saint-Louis Hospital, 75010 Paris, France
| | - Shuang Wu
- National Institute of Health and Medical Research, Medical Research Unit S-1165/Paris Diderot University, University Institute of Hematology, Saint-Louis Hospital, 75010 Paris, France
| | - Limin Huang
- National Institute of Health and Medical Research, Medical Research Unit S-1165/Paris Diderot University, University Institute of Hematology, Saint-Louis Hospital, 75010 Paris, France
| | - Catherine Buquet
- National Institute of Health and Medical Research, Unit 1234/Rouen University, Faculty of Medicine and Pharmacy, 76183 Rouen, France
| | - Rong Shen
- National Institute of Health and Medical Research, Medical Research Unit S-1165/Paris Diderot University, University Institute of Hematology, Saint-Louis Hospital, 75010 Paris, France
| | - Berenice Sanchez-Gonzalez
- Immunochemistry Laboratory I, Immunology Department, National School of Biological Sciences, National Polytechnic Institute, Mexico City 11340, Mexico
| | - Ethel Awilda García Latorre
- Immunochemistry Laboratory I, Immunology Department, National School of Biological Sciences, National Polytechnic Institute, Mexico City 11340, Mexico
| | - Olivier Boyer
- National Institute of Health and Medical Research, Unit 1234/Rouen University, Faculty of Medicine and Pharmacy, 76183 Rouen, France
| | - Remi Varin
- National Institute of Health and Medical Research, Unit 1234/Rouen University, Faculty of Medicine and Pharmacy, 76183 Rouen, France
| | - Luis Antonio Jiménez-Zamudio
- Immunochemistry Laboratory I, Immunology Department, National School of Biological Sciences, National Polytechnic Institute, Mexico City 11340, Mexico
| | - Anne Janin
- National Institute of Health and Medical Research, Medical Research Unit S-1165/Paris Diderot University, University Institute of Hematology, Saint-Louis Hospital, 75010 Paris, France
| | - Jean-Pierre Vannier
- National Institute of Health and Medical Research, Unit 1234/Rouen University, Faculty of Medicine and Pharmacy, 76183 Rouen, France
| | - Hong Li
- National Institute of Health and Medical Research, Unit 1234/Rouen University, Faculty of Medicine and Pharmacy, 76183 Rouen, France
| | - He Lu
- National Institute of Health and Medical Research, Medical Research Unit S-1165/Paris Diderot University, University Institute of Hematology, Saint-Louis Hospital, 75010 Paris, France
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Seelige R, Searles S, Bui JD. Mechanisms regulating immune surveillance of cellular stress in cancer. Cell Mol Life Sci 2018; 75:225-240. [PMID: 28744671 PMCID: PMC11105730 DOI: 10.1007/s00018-017-2597-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 06/28/2017] [Accepted: 07/17/2017] [Indexed: 12/19/2022]
Abstract
The purpose of this review is to explore immune-mediated mechanisms of stress surveillance in cancer, with particular emphasis on the idea that all cancers have classical hallmarks (Hanahan and Weinberg in Cell 100:57-70, 67; Cell 144:646-674, 68) that could be interrelated. We postulate that hallmarks of cancer associated with cellular stress pathways (Luo et al. in Cell 136:823-837, 101) including oxidative stress, proteotoxic stress, mitotic stress, DNA damage, and metabolic stress could define and modulate the inflammatory component of cancer. As such, the overarching goal of this review is to define the types of cellular stress that cancer cells undergo, and then to explore mechanisms by which immune cells recognize, respond to, and are affected by each stress response.
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Affiliation(s)
- Ruth Seelige
- Department of Pathology, University of California, 9500 Gilman Dr MC 0612, La Jolla, CA, 92093-0612, USA
| | - Stephen Searles
- Department of Pathology, University of California, 9500 Gilman Dr MC 0612, La Jolla, CA, 92093-0612, USA
| | - Jack D Bui
- Department of Pathology, University of California, 9500 Gilman Dr MC 0612, La Jolla, CA, 92093-0612, USA.
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44
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Verbaanderd C, Maes H, Schaaf MB, Sukhatme VP, Pantziarka P, Sukhatme V, Agostinis P, Bouche G. Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer agents. Ecancermedicalscience 2017; 11:781. [PMID: 29225688 PMCID: PMC5718030 DOI: 10.3332/ecancer.2017.781] [Citation(s) in RCA: 186] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Indexed: 12/26/2022] Open
Abstract
Chloroquine (CQ) and hydroxychloroquine (HCQ) are well-known 4-aminoquinoline antimalarial agents. Scientific evidence also supports the use of CQ and HCQ in the treatment of cancer. Overall, preclinical studies support CQ and HCQ use in anti-cancer therapy, especially in combination with conventional anti-cancer treatments since they are able to sensitise tumour cells to a variety of drugs, potentiating the therapeutic activity. Thus far, clinical results are mostly in favour of the repurposing of CQ. However, over 30 clinical studies are still evaluating the activity of both CQ and HCQ in different cancer types and in combination with various standard treatments. Interestingly, CQ and HCQ exert effects both on cancer cells and on the tumour microenvironment. In addition to inhibition of the autophagic flux, which is the most studied anti-cancer effect of CQ and HCQ, these drugs affect the Toll-like receptor 9, p53 and CXCR4-CXCL12 pathway in cancer cells. In the tumour stroma, CQ was shown to affect the tumour vasculature, cancer-associated fibroblasts and the immune system. The evidence reviewed in this paper indicates that both CQ and HCQ deserve further clinical investigations in several cancer types. Special attention about the drug (CQ versus HCQ), the dose and the schedule of administration should be taken in the design of new trials.
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Affiliation(s)
- Ciska Verbaanderd
- Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium.,Cell Death Research and Therapy Lab, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.,Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium
| | - Hannelore Maes
- Cell Death Research and Therapy Lab, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
| | - Marco B Schaaf
- Cell Death Research and Therapy Lab, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
| | - Vikas P Sukhatme
- GlobalCures, Inc, Newton, MA 02459, USA.,Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Current address: Emory School of Medicine, Atlanta, GA 30322, USA
| | - Pan Pantziarka
- Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium.,The George Pantziarka TP53 Trust, London KT1 2JP, UK
| | | | - Patrizia Agostinis
- Cell Death Research and Therapy Lab, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
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45
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Jawhari S, Bessette B, Hombourger S, Durand K, Lacroix A, Labrousse F, Jauberteau MO, Ratinaud MH, Verdier M. Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survival. Carcinogenesis 2017; 38:592-603. [PMID: 28402394 DOI: 10.1093/carcin/bgx029] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 03/21/2017] [Indexed: 01/21/2023] Open
Abstract
Glioblastoma multiform (GBM), the most common and aggressive primary brain tumor, is characterized by a high degree of hypoxia and resistance to therapy because of its adaptation capacities, including autophagy and growth factors signaling. In this study, we show an efficient hypoxia-induced survival autophagy in four different GBM cell lines (U87MG, M059K, M059J and LN-18) and an activation of a particular neurotrophin signaling pathway. Indeed, the enhancement of both TrkC and NT-3 was followed by downstream p38MAPK phosphorylation, suggesting the occurrence of a survival autocrine loop. Autophagy inhibition increased the hypoxia-induced expression of TrkC and its phosphorylated form as well as the phosphorylation of p38, suggesting a complementary effect of the two processes, leading to cell survival. Alone, autophagy inhibition reduced cellular growth without inducing cell death. However, the double inhibition of autophagy and TrkC signaling was necessary to bring cells to death as shown by PARP cleavage, particularly important in hypoxia. Moreover, a very high expression of TrkC and NT-3 was found in tumor sections from GBM patients, highlighting the importance of neurotrophic signaling in GBM tumor cell survival. These data suggest that a combined treatment targeting these two pathways could be considered in order to induce the death of GBM cells.
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Affiliation(s)
- Soha Jawhari
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | - Barbara Bessette
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | - Sophie Hombourger
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | - Karine Durand
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | - Aurélie Lacroix
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | - François Labrousse
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | | | | | - Mireille Verdier
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
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Li S, Yang G, Zhu X, Cheng L, Sun Y, Zhao Z. Combination of rapamycin and garlic-derived S-allylmercaptocysteine induces colon cancer cell apoptosis and suppresses tumor growth in xenograft nude mice through autophagy/p62/Nrf2 pathway. Oncol Rep 2017; 38:1637-1644. [DOI: 10.3892/or.2017.5849] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 07/10/2017] [Indexed: 11/06/2022] Open
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Soubannier V, Stifani S. NF-κB Signalling in Glioblastoma. Biomedicines 2017; 5:biomedicines5020029. [PMID: 28598356 PMCID: PMC5489815 DOI: 10.3390/biomedicines5020029] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 06/06/2017] [Accepted: 06/07/2017] [Indexed: 12/11/2022] Open
Abstract
Nuclear factor-κB (NF-κB) is a transcription factor regulating a wide array of genes mediating numerous cellular processes such as proliferation, differentiation, motility and survival, to name a few. Aberrant activation of NF-κB is a frequent event in numerous cancers, including glioblastoma, the most common and lethal form of brain tumours of glial cell origin (collectively termed gliomas). Glioblastoma is characterized by high cellular heterogeneity, resistance to therapy and almost inevitable recurrence after surgery and treatment. NF-κB is aberrantly activated in response to a variety of stimuli in glioblastoma, where its activity has been implicated in processes ranging from maintenance of cancer stem-like cells, stimulation of cancer cell invasion, promotion of mesenchymal identity, and resistance to radiotherapy. This review examines the mechanisms of NF-κB activation in glioblastoma, the involvement of NF-κB in several mechanisms underlying glioblastoma propagation, and discusses some of the important questions of future research into the roles of NF-κB in glioblastoma.
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Affiliation(s)
- Vincent Soubannier
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A2B4, Canada.
| | - Stefano Stifani
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A2B4, Canada.
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Gozuacik D, Akkoc Y, Ozturk DG, Kocak M. Autophagy-Regulating microRNAs and Cancer. Front Oncol 2017; 7:65. [PMID: 28459042 PMCID: PMC5394422 DOI: 10.3389/fonc.2017.00065] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 03/21/2017] [Indexed: 12/12/2022] Open
Abstract
Macroautophagy (autophagy herein) is a cellular stress response and a survival pathway that is responsible for the degradation of long-lived proteins, protein aggregates, as well as damaged organelles in order to maintain cellular homeostasis. Consequently, abnormalities of autophagy are associated with a number of diseases, including Alzheimers’s disease, Parkinson’s disease, and cancer. According to the current view, autophagy seems to serve as a tumor suppressor in the early phases of cancer formation, yet in later phases, autophagy may support and/or facilitate tumor growth, spread, and contribute to treatment resistance. Therefore, autophagy is considered as a stage-dependent dual player in cancer. microRNAs (miRNAs) are endogenous non-coding small RNAs that negatively regulate gene expression at a post-transcriptional level. miRNAs control several fundamental biological processes, and autophagy is no exception. Furthermore, accumulating data in the literature indicate that dysregulation of miRNA expression contribute to the mechanisms of cancer formation, invasion, metastasis, and affect responses to chemotherapy or radiotherapy. Therefore, considering the importance of autophagy for cancer biology, study of autophagy-regulating miRNA in cancer will allow a better understanding of malignancies and lead to the development of novel disease markers and therapeutic strategies. The potential to provide study of some of these cancer-related miRNAs were also implicated in autophagy regulation. In this review, we will focus on autophagy, miRNA, and cancer connection, and discuss its implications for cancer biology and cancer treatment.
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Affiliation(s)
- Devrim Gozuacik
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.,Center of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics (EFSUN), Sabanci University, Istanbul, Turkey
| | - Yunus Akkoc
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
| | - Deniz Gulfem Ozturk
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
| | - Muhammed Kocak
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
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Robainas M, Otano R, Bueno S, Ait-Oudhia S. Understanding the role of PD-L1/PD1 pathway blockade and autophagy in cancer therapy. Onco Targets Ther 2017; 10:1803-1807. [PMID: 28367063 PMCID: PMC5370068 DOI: 10.2147/ott.s132508] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Autophagy is a vital, physiological catabolic process for cell survival by which cells clear damaged organelles and recycle nutrients when homeostasis is maintained. Cancer is a complex disease with uncontrolled growth of cancer cells. Recent studies have suggested the role of autophagy in cancer. A complex relationship exists between autophagy and cancer, since autophagy can contribute to the survival or the destruction of malignant cells depending on the stage of tumor development. In this review, we describe in detail the mechanism underlying autophagy in cancer cells and the intricate involvement of the programmed cell death-1 (PD1) receptor with its ligand (PD-L1). The overexpression of PD-L1 receptors on cancer cell membranes has been observed in several types of cancers. The interaction of PD-L1 on cancer cells with PD1 on the surface of T-cells causes cancer cells to escape from the immune system by preventing the activation of new cytotoxic T-cells in the lymph nodes and subsequent recruitment to the tumor. In addition to its immunopathogenicity, PD1 has been related to autophagy. Reduction of this receptor due to treatment increases autophagy, therefore promoting the recycling of nutrients and clearance of toxic species, consequently promoting cell survival. In addition, PD-L1/PD1 engagement can induce autophagy in nearby T-cells due to a decrease in the amino acids tryptophan and arginine and due to the deprivation of nutrients such as glucose followed by a reduction in glucose metabolism. Resistance to cancer therapies is attributed to various pathways in oncogenesis including, inhibition of tumor suppressors, alteration of the tumor metabolic environment, and upregulation of autophagy. Here we explore the interaction between the immunosuppressive PD-L1/PD1 engagement and autophagy mechanisms, and evaluate the impact of inhibition of these pathways in augmenting antitumor efficacy.
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Affiliation(s)
- Marianela Robainas
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA
| | - Rafael Otano
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA
| | - Stephen Bueno
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA
| | - Sihem Ait-Oudhia
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA
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50
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Wang SF, Wu MY, Cai CZ, Li M, Lu JH. Autophagy modulators from traditional Chinese medicine: Mechanisms and therapeutic potentials for cancer and neurodegenerative diseases. JOURNAL OF ETHNOPHARMACOLOGY 2016; 194:861-876. [PMID: 27793785 DOI: 10.1016/j.jep.2016.10.069] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 10/19/2016] [Accepted: 10/21/2016] [Indexed: 06/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese medicine (TCM), an ancient yet still alive medicinal system widely used in East Asia, has played an essential role in health maintenance and diseases control, for a wide range of human chronic diseases like cancers and neurodegenerative diseases. TCM-derived compounds and extracts attract wide attention for their potential application as therapeutic agents against above mentioned diseases. AIM OF REVIEW Recent years the enthusiasm in searching for autophagy regulators for human diseases has yielded many positive hits. TCM-derived compounds as important sources for drug discovery have been widely tested in different models for autophagy modulation. Here we summarize the current progress in the discovery of natural autophagy regulators from TCM for the therapeutic application in cancer and neurodegenerative disease models, aiming to provide the direct link from traditional use to new pharmacological application. METHODS The present review collected the literature published during the recent 10 years which studied the effect of TCM-derived compounds or extracts on autophagy regulation from PubMed, Web of Science, Google Scholar and Science Direct. The names of chemical compounds studied in this article are corresponding to the information in journal plant list. RESULTS In this review, we give a brief introduction about the autophagy and its roles in cancer and neurodegenerative disease models and describe the molecular mechanisms of autophagy modulation. We also make comprehensive lists to summarize the effects and underlying mechanisms of TCM-derived autophagy regulators in cancer and neurodegenerative disease models. In the end of the review, we discuss the current strategies, problems and future direction for TCM-derived autophagy regulators in the treatment of human diseases. CONCLUSIONS A number of data from in vivo and in vitro models indicated TCM derived compounds and extracts hold great potential for the treatment of human diseases including cancers and neurodegenerative diseases. Autophagy, as a novel and promising drug target involved in a wide range of human diseases, can be modulated by many TCM derived agents, indicating autophagy modulation may be an important mechanism underlying the therapeutic effect of TCM in treating diseases. Furthermore, we look forward to seeing the discovery of ideal autophagy modulators from TCM with considerably higher selectivity for the treatment of human diseases.
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Affiliation(s)
- Sheng-Fang Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
| | - Ming-Yue Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
| | - Cui-Zan Cai
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
| | - Min Li
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong
| | - Jia-Hong Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
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