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ALKhemeiri N, Eljack S, Saber-Ayad MM. Perspectives of Targeting Autophagy as an Adjuvant to Anti-PD-1/PD-L1 Therapy for Colorectal Cancer Treatment. Cells 2025; 14:745. [PMID: 40422248 DOI: 10.3390/cells14100745] [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: 02/13/2025] [Revised: 05/07/2025] [Accepted: 05/12/2025] [Indexed: 05/28/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world, with increasing incidence and mortality rates. Standard conventional treatments for CRC are surgery, chemotherapy, and radiotherapy. Recently, immunotherapy has been introduced as a promising alternative to CRC treatment that utilizes patients' immune system to combat cancer cells. The beneficial effect of immune checkpoint inhibitors, specifically anti-PD-1/ PD-L1, has been ascribed to the abundance of DNA replication errors that result in the formation of neoantigens. Such neoantigens serve as distinct flags that amplify the immune response when checkpoint inhibitors (ICIs) are administered. DNA replication errors in CRC patients are expressed as two statuses: the first is the deficient mismatch repair (MSI-H/dMMR) with a higher overall immune response and survival rate than the second status of patients with proficient mismatch repair (MSS/pMMR). There is a limitation to using anti-PD-1/PD-L1 as it is only confined to MSI-H/dMMR, where there is an abundance of T-cell inhibitory ligands (PD-L1). This calls for investigating new therapeutic interventions to widen the scope of ICIs' role in the treatment of CRC. Autophagy modulation provides a good example. Autophagy is a cellular process that plays a crucial role in maintaining cellular homeostasis and has been studied for its impact on tumor development, progression, and response to treatment. In this review, we aim to highlight autophagy as a potential determinant in tumor immune response and to study the impact of autophagy on the tumor immune microenvironment. Moreover, we aim to investigate the value of a combination of anti-PD-1/PD-L1 agents with autophagy modulators as an adjuvant therapeutic approach for CRC treatment.
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Affiliation(s)
- Nasrah ALKhemeiri
- College of Graduate Studies, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
| | - Sahar Eljack
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Department of Pharmaceutics, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan
| | - Maha Mohamed Saber-Ayad
- College of Graduate Studies, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Department of Pharmacology, Faculty of Medicine, Cairo University, Cairo 12211, Egypt
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Lei X, Zheng Y, Su W. RNA-binding proteins and autophagy in lung cancer: mechanistic insights and therapeutic perspectives. Discov Oncol 2025; 16:599. [PMID: 40272614 PMCID: PMC12022210 DOI: 10.1007/s12672-025-02413-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 04/16/2025] [Indexed: 04/27/2025] Open
Abstract
BACKGROUND Lung cancer remains a leading cause of cancer-related mortality worldwide. Its progression is intricately associated with the dynamic regulation of autophagy and RNA-binding proteins (RBPs), which play crucial roles in mRNA stability, alternative splicing, and cellular stress responses. OBJECTIVES This review aims to systematically analyze the mechanisms through which RBPs and autophagy contribute to lung cancer progression and explore potential therapeutic strategies targeting these pathways. METHODS We reviewed recent studies on the molecular mechanisms by which RBPs regulate tumor proliferation, metabolic adaptation, and their interaction with autophagy. The review also examines the dual roles of autophagy in lung cancer, highlighting its context-dependent effects on cell survival and death. RESULTS The interactions and regulatory networks between RBPs and autophagy involve multiple levels of regulation. RBPs can directly influence autophagy processes and act as microRNA (miRNA) sponges to regulate mRNA stability. The modulation of RBPs affects the expression of autophagy-related genes (ATGs) and autophagosome formation. Additionally, RBPs participate in complex regulatory interactions with non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and other proteins. CONCLUSIONS This review proposes innovative therapeutic strategies that combine RBP-targeting approaches (e.g., small molecule inhibitors, CRISPR gene editing) with autophagy modulators (e.g., mTOR inhibitors, chloroquine) to enhance treatment efficacy. Nanoparticle drug delivery systems and epigenetic regulation offer further opportunities for targeted interventions. This review lays a theoretical foundation for advancing lung cancer research and provides novel insights into synergistic therapies that target both RBPs and autophagy to improve treatment outcomes for lung cancer.
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Affiliation(s)
- Xiao Lei
- Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China
- Zhanjiang Key Laboratory of Tumor Microenvironment and Organoid Research, Zhanjiang, 524001, China
- Department of Guangdong Medical University, Zhanjiang, 524023, China
| | - Yuexin Zheng
- Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China
- Zhanjiang Key Laboratory of Tumor Microenvironment and Organoid Research, Zhanjiang, 524001, China
- Department of Guangdong Medical University, Zhanjiang, 524023, China
| | - Wenmei Su
- Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China.
- Zhanjiang Key Laboratory of Tumor Microenvironment and Organoid Research, Zhanjiang, 524001, China.
- Department of Guangdong Medical University, Zhanjiang, 524023, China.
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Yibcharoenporn C, Muanprasat C, Moonwiriyakit A, Satitsri S, Pathomthongtaweechai N. AMPK in Intestinal Health and Disease: A Multifaceted Therapeutic Target for Metabolic and Inflammatory Disorders. Drug Des Devel Ther 2025; 19:3029-3058. [PMID: 40291159 PMCID: PMC12024487 DOI: 10.2147/dddt.s507489] [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: 11/27/2024] [Accepted: 04/04/2025] [Indexed: 04/30/2025] Open
Abstract
The intestines play essential roles in nutrient absorption and immune function and help maintain a protective barrier. Disruptions to its function can result in various diseases, including metabolic disorders, inflammation, and cancer. As a key regulator of cellular energy levels, 5'-adenosine monophosphate-activated protein kinase (AMPK) is essential for intestinal health. Beyond its established metabolic role, emerging evidence suggests that AMPK exerts profound effects on intestinal cell physiology, influencing cell proliferation and differentiation, inflammation, autophagy, barrier integrity, and smooth muscle contractility. Here, we explore the structure and regulation of AMPK, as well as its diverse roles in intestinal diseases and potential as a therapeutic target. Our findings reveal that AMPK is a multifaceted regulator of intestinal health, modulating various cellular processes and intestinal diseases. It plays a dual role in cancer, acting as both a tumor suppressor and promoter, and it regulates inflammatory pathways, autophagy, tight junction formation, and smooth muscle contractility. Both natural and synthetic AMPK activators offer promise as therapeutic agents. This review of AMPK's mechanisms and activators offers valuable insights for developing novel therapies for intestinal disorders. Further research is needed to fully define AMPK's roles and therapeutic potential.
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Affiliation(s)
- Chamnan Yibcharoenporn
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, 10540, Thailand
| | - Chatchai Muanprasat
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, 10540, Thailand
| | - Aekkacha Moonwiriyakit
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, 10540, Thailand
| | - Saravut Satitsri
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, 10540, Thailand
| | - Nutthapoom Pathomthongtaweechai
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, 10540, Thailand
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Tao D, Li F, Zhang X, Guo H, Yang R, Yang Y, Zhang L, Shen Z, Teng J, Chen P, He B. 20(R)-ginsenoside Rg3 protects against focal cerebral ischemia‒reperfusion injury by suppressing autophagy via PI3K/Akt/mTOR signaling pathway. Neuropharmacology 2025; 263:110226. [PMID: 39557153 DOI: 10.1016/j.neuropharm.2024.110226] [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: 07/08/2024] [Revised: 10/29/2024] [Accepted: 11/14/2024] [Indexed: 11/20/2024]
Abstract
OBJECTIVE This study aimed to investigate the effect of 20(R)-ginsenoside Rg3 on autophagy induced by cerebral ischemia‒reperfusion injury (CIRI) in rats and explore its regulation of the PI3K/Akt signaling pathway. METHODS Middle cerebral artery occlusion/reperfusion (MCAO/R) in male rats was injected intraperitoneally with 20(R)-ginsenoside Rg3 (5, 10, 20 mg/kg) 12 h before modeling, 2 h after ischemia and 12 h after reperfusion. Neurobehavioral and neuronal morphological changes were detected 24 h after brain I/R. In vitro, the OGD/R-induced injury model is replicated in PC12 cells and different concentrations of 20(R)-ginsenoside Rg3 are administered to observe its effects on cell viability and autophagy and PI3K/Akt/mTOR-related protein expression. RESULTS Our findings suggest that treatment with 20 mg/kg 20(R)-ginsenoside Rg3 significantly attenuated the neuronal injury, as evidenced by a decreased number of damaged neurons, reduced dissolution of Nissl corpuscles, a fewer autophagosomes, and downregulated expression of Beclin1 and LC3-II/I compared with the MCAO/R group. Furthermore, 20(R)-ginsenoside Rg3 treatment significantly upregulated the expression of p62, p-PI3K, p-AKT, and p-mTOR. In vitro, 20(R)-ginsenoside Rg3 significantly improved the survival rate of cells following OGD/R and markedly attenuated the LY294002 and OGD/R-induced upregulation of Beclin1 and LC3 gene expression. Moreover, 20(R)-ginsenoside Rg3 could rescued the LY294002 and OGD/R-induced downregulation of p62, p-PI3K, p-AKT, and p-mTOR expression. CONCLUSIONS 20(R)-ginsenoside Rg3 attenuates neuronal injury and motor dysfunction following ischemia-reperfusion by inhibiting the activation of autophagy, and its mechanism is related to the upregulation of the PI3K/Akt/mTOR signaling pathway.
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Affiliation(s)
- Daiju Tao
- School of Pharmaceutical Science, Yunnan Key Laboratory of Pharmacology for Natural Products, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, PR China
| | - Fajing Li
- School of Pharmaceutical Science, Yunnan Key Laboratory of Pharmacology for Natural Products, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, PR China; The First People's Hospital of Liangshan Yi Autonomous Prefecture, XiChang, Sichuan Province, 615000, PR China
| | - Xiaochao Zhang
- School of Pharmaceutical Science, Yunnan Key Laboratory of Pharmacology for Natural Products, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, PR China
| | - Hui Guo
- School of Pharmaceutical Science, Yunnan Key Laboratory of Pharmacology for Natural Products, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, PR China; Department of Pharmacology, Haiyuan College, Kunming Medical University, 650106, PR China
| | - Renhua Yang
- School of Pharmaceutical Science, Yunnan Key Laboratory of Pharmacology for Natural Products, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, PR China
| | - Yuan Yang
- School of Pharmaceutical Science, Yunnan Key Laboratory of Pharmacology for Natural Products, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, PR China
| | - Li Zhang
- School of Pharmaceutical Science, Yunnan Key Laboratory of Pharmacology for Natural Products, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, PR China
| | - Zhiqiang Shen
- School of Pharmaceutical Science, Yunnan Key Laboratory of Pharmacology for Natural Products, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, PR China
| | - Jia Teng
- School of Pharmaceutical Science, Yunnan Key Laboratory of Pharmacology for Natural Products, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, PR China; Department of Pharmacology, Haiyuan College, Kunming Medical University, 650106, PR China.
| | - Peng Chen
- School of Pharmaceutical Science, Yunnan Key Laboratory of Pharmacology for Natural Products, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, PR China.
| | - Bo He
- School of Pharmaceutical Science, Yunnan Key Laboratory of Pharmacology for Natural Products, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, PR China.
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YIN YUQIN, WU YU, HUANG HONGLIANG, DUAN YINGYING, YUAN ZHONGWEN, CAO LIHUI, YING JINJIN, ZHOU YONGHENG, FENG SENLING. The superiority of PMFs on reversing drug resistance of colon cancer and the effect on aerobic glycolysis-ROS-autophagy signaling axis. Oncol Res 2024; 32:1891-1902. [PMID: 39574478 PMCID: PMC11576955 DOI: 10.32604/or.2024.048778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 02/28/2024] [Indexed: 11/24/2024] Open
Abstract
Background Polymethoxylated flavones (PMFs) are compounds present in citrus peels and other Rutaceae plants, which exhibit diverse biological activities, including robust antitumor and antioxidant effects. However, the mechanism of PMFs in reversing drug resistance to colon cancer remains unknown. In the present study, we aimed to investigate the potential connection between the aerobic glycolysis-ROS-autophagy signaling axis and the reversal of PTX resistance in colon cancer by PMFs. Methods MTT Cell viability assay and colony formation assay were used to investigate the effect of PMFs combined with PTX in reversing HCT8/T cell resistance ex vivo; the mRNA and protein levels of the target were detected by SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), quantitative real-time fluorescence polymerase chain reaction (qRT-PCR) and Western blot protein immunoblotting (WB); An HCT8/T cell xenograft model was established to investigate the MDR reversal activity of PMFs in vivo; The extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) were detected to assess the cellular oxygen consumption rate and glycolytic process. Results HCT8/T cells demonstrated significant resistance to PTX, up-regulating the expression levels of ABCB1 mRNA, P-gp, LC3-I, and LC3-II protein, and increasing intracellular reactive oxygen species (ROS) content. PMFs mainly contain two active ingredients, nobiletin, and tangeretin, which were able to reverse drug resistance in HCT8/T cells in a concentration-dependent manner. PMFs exhibited high tolerance in the HCT8/T nude mouse model while increasing the sensitivity of PTX-resistant cells and suppressing tumor growth significantly. PMFs combined with PTX reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in HCT8/T cells. Additionally, PMFs reduced intracellular ROS content, down-regulated the expression levels of autophagy-related proteins LC3-I, LC3-II, Beclin1, and ATG7, and significantly reduced the number of autophagosomes in HCT8/T cells. Conclusions The present study demonstrated that PMFs could potentially reverse PTX resistance in colon cancer by regulating the aerobic glycolysis-ROS-autophagy signaling axis, which indicated that PMFs would be potential potentiators for future chemotherapeutic agents in colon cancer.
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Affiliation(s)
- YUQIN YIN
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - YU WU
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - HONGLIANG HUANG
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - YINGYING DUAN
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - ZHONGWEN YUAN
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - LIHUI CAO
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - JINJIN YING
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - YONGHENG ZHOU
- Department of Pharmacy, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 511300, China
| | - SENLING FENG
- Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
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Lee M, Kim HG. Anti-Cancer Strategy Based on Changes in the Role of Autophagy Depending on the Survival Environment and Tumorigenesis Stages. Molecules 2024; 29:5134. [PMID: 39519774 PMCID: PMC11547988 DOI: 10.3390/molecules29215134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/21/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Autophagy is a crucial mechanism for recycling intracellular materials, and under normal metabolic conditions, it is maintained at low levels in cells. However, when nutrients are deficient or under hypoxic conditions, the level of autophagy significantly increases. Particularly in cancer cells, which grow more rapidly than normal cells and tend to grow in a three-dimensional manner, cells inside the cell mass often face limited oxygen supply, leading to inherently higher levels of autophagy. Therefore, the initial development of anticancer drugs targeting autophagy was based on a strategy to suppress these high levels of autophagy. However, anticancer drugs that inhibit autophagy have not shown promising results in clinical trials, as it has been revealed that autophagy does not always play a role that favors cancer cell survival. Hence, this review aims to suggest anticancer strategies based on the changes in the role of autophagy according to survival conditions and tumorigenesis stage.
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Affiliation(s)
- Michael Lee
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Republic of Korea
- Institute for New Drug Development, Incheon National University, Incheon 22012, Republic of Korea
| | - Hye-Gyo Kim
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Republic of Korea
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Zhao Y, Si S, Ren Y, Wu X, Zhang Z, Tian Y, Li J, Li Y, Hou M, Yao X, Xu Z, Jiang R, Kang X, Gong Y, Li Q, Tian Y. Marine red yeast supplementation improves laying performance by regulating small intestinal homeostasis in aging chickens. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2024; 18:177-190. [PMID: 39263442 PMCID: PMC11388669 DOI: 10.1016/j.aninu.2024.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 02/25/2024] [Accepted: 04/03/2024] [Indexed: 09/13/2024]
Abstract
Recent studies have shown that age-related aging evolution is accompanied by imbalances in intestinal homeostasis. Marine red yeast (MRY) is a functional probiotic that has been shown to have antioxidant, immune and other properties. Therefore, we chose 900 healthy Hy-Line Brown hens at 433 d old as the research subjects and evaluated the correlation between intestinal health, laying performance, and egg quality in aged hens through the supplementation of MRY. These laying hens were assigned into 5 groups and received diet supplementation with 0%, 0.5%, 1.0%, 1.5%, and 2% MRY for 12 weeks. The results showed that MRY supplementation increased egg production rate, average egg weight, and egg quality, and decreased feed conversion ratio and daily feed intake (P < 0.05). The MRY supplement improved antioxidant indicators such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), stimulated villus height, and increased the villus height to crypt depth ratio (V/C ratio) in the intestine (P < 0.05). It also regulated the expression of intestinal inflammatory factors (transforming growth factor-β [TGF-β], interleukin [IL]-1β, IL-8, tumor necrosis factor-α [TNF-α]) while increasing serum immunoglobulin G (IgG) levels (P < 0.05). Furthermore, MRY supplementation upregulated the mRNA expression of tight junction proteins (occludin and zonula occludens-1 [ZO-1]), anti-apoptotic gene (Bcl-2), and autophagy-related proteins (beclin-1 and light chain 3I [LC3I]) in the intestine (P < 0.05). The MRY supplement also led to an increase in the concentration of short-chain fatty acids in the cecum, and the relative abundance of the phylum Bacteroidetes, and genera Bacteroides and Rikenellaceae_RC9_gut_group. The LEfSe analysis revealed an enrichment of Sutterella and Akkermansia muciniphila. In conclusion, the results of this experiment indicated that the additional supplementation of MRY can improve the production performance of laying hens and may contribute to the restoration and balance of intestinal homeostasis, which supports the application potential of MRY as a green and efficient feed additive for improving the laying performance in chickens.
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Affiliation(s)
- Yudian Zhao
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Sujin Si
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Yangguang Ren
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Xing Wu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Zihao Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Yixiang Tian
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang 453003, China
| | - Jing Li
- AB Vista, Marlborough SN8 4AN, UK
| | - Yijie Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Meng Hou
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Xueyang Yao
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Zhaoheng Xu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Ruirui Jiang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Xiangtao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Yujie Gong
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Qiang Li
- Henan College of Animal Husbandry and Economics, Zhengzhou 450046, China
| | - Yadong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
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Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:9463. [PMID: 39273409 PMCID: PMC11395697 DOI: 10.3390/ijms25179463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.
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Affiliation(s)
- Ehsan Gharib
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| | - Gilles A Robichaud
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
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Zhuang ZJ, Li FJ, Lv D, Duan HQ, Chen LY, Chen P, Shen ZQ, He B. Regulation of Autophagy Signaling Pathways by Ginseng Saponins: A Review. Chem Biodivers 2024; 21:e202400934. [PMID: 38898600 DOI: 10.1002/cbdv.202400934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/17/2024] [Accepted: 06/18/2024] [Indexed: 06/21/2024]
Abstract
Ginseng saponins (ginsenosides), bioactive compounds derived from ginseng, are widely used natural products with potent therapeutic properties in the management of various ailments, particularly tumors, cardiovascular and cerebrovascular diseases, and immune system disorders. Autophagy, a highly regulated and multistep process involving the breakdown of impaired organelles and macromolecules by autophagolysosomes and autophagy-related genes (ATGs), has gained increasing attention as a potential target for ginsenoside-mediated disease treatment. This review aims to provide a comprehensive overview of recent research advances in the understanding of autophagy-related signaling pathways and the role of ginsenoside-mediated autophagy regulation. By delving into the intricate autophagy signaling pathways underpinning the pharmacological properties of ginsenosides, we highlight their therapeutic potential in addressing various conditions. Our findings serve as a comprehensive reference for further investigation into the medicinal properties of ginseng or ginseng-related products.
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Affiliation(s)
- Zhu-Jun Zhuang
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products/College of Modern Biomedical Industry, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, People's Republic of China
| | - Fa-Jing Li
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products/College of Modern Biomedical Industry, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, People's Republic of China
- The First People's Hospital of Liangshan Prefecture, Sichuan, 615000, People's Republic of China
| | - Di Lv
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products/College of Modern Biomedical Industry, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, People's Republic of China
| | - Heng-Qian Duan
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products/College of Modern Biomedical Industry, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, People's Republic of China
| | - Lin-Yi Chen
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products/College of Modern Biomedical Industry, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, People's Republic of China
| | - Peng Chen
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products/College of Modern Biomedical Industry, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, People's Republic of China
| | - Zhi-Qiang Shen
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products/College of Modern Biomedical Industry, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, People's Republic of China
| | - Bo He
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products/College of Modern Biomedical Industry, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, 650500, People's Republic of China
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NAGINI SIDDAVARAM, KALLAMADI PRATHAPREDDY, TANAGALA KRANTHIKIRANKISHORE, REDDY GEEREDDYBHANUPRAKASH. Aldo-keto reductases: Role in cancer development and theranostics. Oncol Res 2024; 32:1287-1308. [PMID: 39055885 PMCID: PMC11267078 DOI: 10.32604/or.2024.049918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 05/08/2024] [Indexed: 07/28/2024] Open
Abstract
Aldo-keto reductases (AKRs) are a superfamily of enzymes that play crucial roles in various cellular processes, including the metabolism of xenobiotics, steroids, and carbohydrates. A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers. AKRs are aberrantly expressed in a wide range of malignant tumors. Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance. AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression. Inhibition of aldose reductase (AR), either alone or in combination with chemotherapeutic drugs, has evolved as a pragmatic therapeutic option for cancer. Several classes of synthetic aldo-keto reductase (AKR) inhibitors have been developed as potential anticancer agents, some of which have shown promise in clinical trials. Many AKR inhibitors from natural sources also exhibit anticancer effects. Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies. These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy. In this review, we discuss the physiological functions of human AKRs, the aberrant expression of AKRs in malignancies, the involvement of AKRs in the acquisition of cancer hallmarks, and the role of AKRs in oncogenic signaling, and drug resistance. Finally, the potential of aldose reductase inhibitors (ARIs) as anticancer drugs is summarized.
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Hassan AMIA, Zhao Y, Chen X, He C. Blockage of Autophagy for Cancer Therapy: A Comprehensive Review. Int J Mol Sci 2024; 25:7459. [PMID: 39000565 PMCID: PMC11242824 DOI: 10.3390/ijms25137459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/25/2024] [Accepted: 07/03/2024] [Indexed: 07/16/2024] Open
Abstract
The incidence and mortality of cancer are increasing, making it a leading cause of death worldwide. Conventional treatments such as surgery, radiotherapy, and chemotherapy face significant limitations due to therapeutic resistance. Autophagy, a cellular self-degradation mechanism, plays a crucial role in cancer development, drug resistance, and treatment. This review investigates the potential of autophagy inhibition as a therapeutic strategy for cancer. A systematic search was conducted on Embase, PubMed, and Google Scholar databases from 1967 to 2024 to identify studies on autophagy inhibitors and their mechanisms in cancer therapy. The review includes original articles utilizing in vitro and in vivo experimental methods, literature reviews, and clinical trials. Key terms used were "Autophagy", "Inhibitors", "Molecular mechanism", "Cancer therapy", and "Clinical trials". Autophagy inhibitors such as chloroquine (CQ) and hydroxychloroquine (HCQ) have shown promise in preclinical studies by inhibiting lysosomal acidification and preventing autophagosome degradation. Other inhibitors like wortmannin and SAR405 target specific components of the autophagy pathway. Combining these inhibitors with chemotherapy has demonstrated enhanced efficacy, making cancer cells more susceptible to cytotoxic agents. Clinical trials involving CQ and HCQ have shown encouraging results, although further investigation is needed to optimize their use in cancer therapy. Autophagy exhibits a dual role in cancer, functioning as both a survival mechanism and a cell death pathway. Targeting autophagy presents a viable strategy for cancer therapy, particularly when integrated with existing treatments. However, the complexity of autophagy regulation and the potential side effects necessitate further research to develop precise and context-specific therapeutic approaches.
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Affiliation(s)
| | - Yuxin Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR 999078, China (X.C.)
| | - Xiuping Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR 999078, China (X.C.)
- Department of Pharmaceutical Science, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR 999078, China
| | - Chengwei He
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR 999078, China (X.C.)
- Department of Pharmaceutical Science, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR 999078, China
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Műzes G, Sipos F. Inflammasomes Are Influenced by Epigenetic and Autophagy Mechanisms in Colorectal Cancer Signaling. Int J Mol Sci 2024; 25:6167. [PMID: 38892354 PMCID: PMC11173330 DOI: 10.3390/ijms25116167] [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: 04/28/2024] [Revised: 05/31/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024] Open
Abstract
Inflammasomes contribute to colorectal cancer signaling by primarily inducing inflammation in the surrounding tumor microenvironment. Its role in inflammation is receiving increasing attention, as inflammation has a protumor effect in addition to inducing tissue damage. The inflammasome's function is complex and controlled by several layers of regulation. Epigenetic processes impact the functioning or manifestation of genes that are involved in the control of inflammasomes or the subsequent signaling cascades. Researchers have intensively studied the significance of epigenetic mechanisms in regulation, as they encompass several potential therapeutic targets. The regulatory interactions between the inflammasome and autophagy are intricate, exhibiting both advantageous and harmful consequences. The regulatory aspects between the two entities also encompass several therapeutic targets. The relationship between the activation of the inflammasome, autophagy, and epigenetic alterations in CRC is complex and involves several interrelated pathways. This article provides a brief summary of the newest studies on how epigenetics and autophagy control the inflammasome, with a special focus on their role in colorectal cancer. Based on the latest findings, we also provide an overview of the latest therapeutic ideas for this complex network.
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Affiliation(s)
- Györgyi Műzes
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary
| | - Ferenc Sipos
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary
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13
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Yu Q, Ding J, Li S, Li Y. Autophagy in cancer immunotherapy: Perspective on immune evasion and cell death interactions. Cancer Lett 2024; 590:216856. [PMID: 38583651 DOI: 10.1016/j.canlet.2024.216856] [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: 03/04/2024] [Revised: 03/22/2024] [Accepted: 04/02/2024] [Indexed: 04/09/2024]
Abstract
Both the innate and adaptive immune systems work together to produce immunity. Cancer immunotherapy is a novel approach to tumor suppression that has arisen in response to the ineffectiveness of traditional treatments like radiation and chemotherapy. On the other hand, immune evasion can diminish immunotherapy's efficacy. There has been a lot of focus in recent years on autophagy and other underlying mechanisms that impact the possibility of cancer immunotherapy. The primary feature of autophagy is the synthesis of autophagosomes, which engulf cytoplasmic components and destroy them by lysosomal degradation. The planned cell death mechanism known as autophagy can have opposite effects on carcinogenesis, either increasing or decreasing it. It is autophagy's job to maintain the balance and proper functioning of immune cells like B cells, T cells, and others. In addition, autophagy controls whether macrophages adopt the immunomodulatory M1 or M2 phenotype. The ability of autophagy to control the innate and adaptive immune systems is noteworthy. Interleukins and chemokines are immunological checkpoint chemicals that autophagy regulates. Reducing antigen presentation to induce immunological tolerance is another mechanism by which autophagy promotes cancer survival. Therefore, targeting autophagy is of importance for enhancing potential of cancer immunotherapy.
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Affiliation(s)
- Qiang Yu
- Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China
| | - Jiajun Ding
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China
| | - Shisen Li
- Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China
| | - Yunlong Li
- Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China.
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Moulana MS, Haiaty S, Bazmani A, Shabkhizan R, Moslehian MS, Sadeghsoltani F, Mostafazadeh M, Asadi MR, Talebi M, Jafari Z, Morovati MR, Farzaei MH, Rahbarghazi R. Tumoricidal properties of thymoquinone on human colorectal adenocarcinoma cells via the modulation of autophagy. BMC Complement Med Ther 2024; 24:132. [PMID: 38532470 DOI: 10.1186/s12906-024-04432-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Colorectal cancer (CRC) is deadly anaplastic changes in the gastrointestinal tract with high-rate mortality. In recent years, the application of phytocompounds has been extended along with different therapeutic protocols. Here, we monitored the effects of Thymoquinone (TQ) on autophagy via mitochondrial function after modulation of the Wnt/β-catenin signaling pathway.Human colorectal adenocarcinoma HT-29 cells were treated with TQ (60 µM) and 15 µM Wnt3a inhibitor (LGK974) for 48 h. The survival rate was evaluated using an MTT assay. The expression of Wnt-related factors (c-Myc, and Axin), angiogenesis (VE-Cadherin), and mitophagy-related factors (PINK1, OPTN) was assessed using real-time PCR assay. Protein levels of autophagy factors (Beclin-1, LC3, and P62) were monitored using western blotting. Using flow cytometry analysis, the intracellular accumulation of Rhodamine 123 was evaluated. The migration properties were analyzed using a scratch wound healing assay.Data indicated that TQ can reduce the viability of HT-29 cells compared to the control cells (p < 0.05). The expression of VE-Cadherin was inhibited while the expression of PINK1 was induced in treated cells (p < 0.05). Both LGK974 and TQ-treated cells exhibited activation of autophagy flux (Beclin-1↑, LC3II/I↑, and p62↓) compared to the control group (p < 0.05). TQ can increase intracellular accumulation of Rhodamine 123, indicating the inhibition of efflux mechanisms in cancer cells. Along with these changes, the migration of cells was also reduced (p < 0.05).TQ is a potential phytocompound to alter the dynamic growth of human colorectal HT-29 cells via the modulation of autophagy, and mitophagy-related mechanisms.
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Affiliation(s)
- Mohammad Saleh Moulana
- Department of Persian Medicine, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sanya Haiaty
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Bazmani
- Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roya Shabkhizan
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marziyeh Sadat Moslehian
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Sadeghsoltani
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mostafa Mostafazadeh
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Asadi
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Talebi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Jafari
- Department of Persian Medicine, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Reza Morovati
- Department of Persian Medicine, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Department of Traditional Pharmacy, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Gadallah MS, Dawoud M, Abdou A. The Role of Beclin 1 and HER2 in Colorectal Carcinoma; An Immunohistochemical Study. Asian Pac J Cancer Prev 2024; 25:617-626. [PMID: 38415549 PMCID: PMC11077107 DOI: 10.31557/apjcp.2024.25.2.617] [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: 10/12/2023] [Accepted: 02/18/2024] [Indexed: 02/29/2024] Open
Abstract
OBJECTIVE This study aimed to evaluate the expression of Beclin 1 and HER2 proteins using immunohistochemistry in CRC tissues compared to colonic adenoma, and to investigate the correlation of their expression with clinicopathological parameters and survival outcomes in CRC patients. METHODS The study utilized paraffin-embedded blocks from 17 colonic adenoma and 81 CRC cases. Immunohistochemical analysis was performed to assess the expression of Beclin 1 and HER2 proteins. RESULTS The cytoplasmic expression of Beclin 1 was significantly higher in CRC tissues compared to adenoma specimens (P=0.051). High Beclin 1 expression was significantly associated with distal colon location (P=0.028). High HER2 cytoplasmic expression was significantly associated with vascular invasion (P=0.05), perineural invasion (P=0.03), and shorter overall survival (P=0.035). CONCLUSIONS The findings suggest that Beclin 1 plays a role in colorectal carcinogenesis, with higher expression observed in CRC cases compared to adenoma cases. Furthermore, HER2 carries poor prognostic impact in CRC cases.
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Affiliation(s)
- Marwa Salah Gadallah
- Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt.
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Alian DME, Helmy MW, Haroun M, Moussa N. Modulation of autophagy and apoptosis can contribute to the anticancer effect of Abemaciclib/Celecoxib combination in colon cancer cells. Med Oncol 2024; 41:43. [PMID: 38170401 PMCID: PMC10764487 DOI: 10.1007/s12032-023-02288-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024]
Abstract
Drug resistance and recurrence represent a great challenge in colorectal cancer management, highlighting the urgent need for novel therapeutics. Our objective is to evaluate the influence of Abemaciclib, Celecoxib, and their combination on both the autophagic and apoptotic machinery in an attempt to unravel the interplay between them in HCT-116 and Caco-2 cell lines. The MTT assay was used to assess the GI50 of the drugs. ELIZA was used to determine the protein levels of Beclin-1, LC3, Cox-2, and Bcl-2. Active Caspase-3 was determined by a colorimetric assay. Gene expression levels of ATG5, LC3, Beclin-1, and p62 were assessed by quantitative real-time PCR. In HCT-116 cells, the GI50s for Abemaciclib and Celecoxib were 15.86 and 92.67 μM, respectively, while for Caco-2 cells, the GI50s were 7.85 and 49.02 μM for Abemaciclib and Celecoxib, respectively. Upon treatment of HCT-116 and Caco-2 cells with Abemaciclib, Celecoxib, and their combinations, ATG5, p62, LC3, and Beclin-1 gene expression levels were up-regulated. The protein levels of Beclin-1, LC3, and Caspase-3 were significantly increased, while Bcl-2 was decreased in both cell lines due to single and combined treatments. Both drugs, either alone or in combination, decreased the migration ability of the cells in both cell lines. To conclude, the treatment protocol has the potential to induce cell cycle arrest, diminish the potentiality of cells for migration, and initiate apoptotic and autophagic cell death. Further research is recommended to unravel the potential antitumor effects of Abemaciclib/Celecoxib combination in different cancer types.
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Affiliation(s)
- Dalia Mohamed Elsayed Alian
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt.
| | - Maged W Helmy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhur University, Damanhur, Egypt
| | - Medhat Haroun
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt
| | - Nermine Moussa
- Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt
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Wang Y, Zhao T, Huang C, Liu F, Zhang Y, Kong D, Fan Z. Effect and mechanism of Banxia Xiexin decoction in colorectal cancer: A network pharmacology approach. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 123:155174. [PMID: 38039904 DOI: 10.1016/j.phymed.2023.155174] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 10/07/2023] [Accepted: 10/29/2023] [Indexed: 12/03/2023]
Abstract
BACKGROUND Banxia Xiexin decoction (BXD) is a traditional Chinese medicine with anti-colorectal cancer (CRC) activity. However, its bioactive constituents and its mechanism of action remain unclear. Herein, we explored the mechanism of action of BXD against CRC using a network pharmacology approach. METHODS First, the targets of the main chemical components of BXD were predicted and collected through a database, and the intersection of compound targets and disease targets was obtained. Subsequently, protein-protein interaction network analysis, Gene Ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to explore the potential mechanisms underlying the effects of BXD on CRC. Finally, a CRC cell model and a CRC xenograft model in nude mice were utilized to further determine the mechanism of action. RESULTS A compound-therapeutic target network of BXD was constructed, revealing 146 cellular targets of BXD. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling axis was identified as the main target of BXD. Using in vitro and in vivo models, the activity of BXD against CRC was found to be mediated through ferritinophagy by targeting the PI3K/AKT/mTOR axis, leading to intracellular iron accumulation, reactive oxygen species activation, and finally ferroptosis. CONCLUSIONS Through the application of network pharmacology and in vitro/in vivo validation experiments, we discovered that BXD exerts anti-CRC effects via the ferritinophagy pathway. Furthermore, we elucidated the potential mechanism underlying its induction of ferritinophagy. These findings demonstrate the significant potential of traditional drugs in managing CRC and support their wider clinical application in combination chemotherapy, targeted therapy, and immunotherapy.
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Affiliation(s)
- Yi Wang
- Colon and Rectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China
| | - Tong Zhao
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Chuyue Huang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Clinical Innovation Center For Anorectal Diseases of T.C.M, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China
| | - Fei Liu
- Colon and Rectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China
| | - Yang Zhang
- Colon and Rectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China.
| | - Desong Kong
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China; Jiangsu Clinical Innovation Center For Anorectal Diseases of T.C.M, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China.
| | - Zhimin Fan
- Colon and Rectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China; Jiangsu Clinical Innovation Center For Anorectal Diseases of T.C.M, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China.
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Shirvalilou S, Khoee S, Khoei S, Karimi MR, Sadri E, Shirvaliloo M. Targeted magnetochemotherapy modified by 5-Fu-loaded thermally on/off switching nanoheaters for the eradication of CT26 murine colon cancer by inducing apoptotic and autophagic cell death. Cancer Nanotechnol 2023. [DOI: 10.1186/s12645-023-00164-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
AbstractDespite significant breakthroughs in diagnosis and treatment of colorectal cancer (CRC), the extent of morbidity and mortality secondary to CRC is still concerning. In this study, we evaluated the efficacy of our new tumor-selective nanoplatforms at induction of apoptosis and autophagy, which was tested using active 5-fluorouracil (5-Fu)-based targeting of tumor cells in a BALB/c murine model of CRC combined with magnetic thermal therapy. Nanoparticles were synthesized and characterized by zeta sizer, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The cytotoxicity and tissue uptake of 5-Fu-loaded folic acid (Fa)-modified magnetic nanoparticles (5-Fu/MNPs-Fa) was assessed using MTT, ICP-OES, and HPLC. The rate of apoptosis and autophagy, as two major indicators of antitumor activity, was measured based on protein expression of Bax, Bcl2, Caspase 3, mTOR, P-mTOR, Beclin-1, and LC3B in CT-26 murine CRC, along with tumor volume and survival time. The spherical 5-Fu/MNPs-Fa exhibited sustained thermal on/off switching drug release and higher therapeutic index compared to free 5-Fu. Our de novo synthetized magnetic nanoheaters successfully delivered the therapeutic agent to the tumor site, enhanced the conversion of radio frequency energy to heat in tumor cells, exhibited higher antitumor efficiency based on Bax/Bcl2 ratio and overexpression of Beclin-1 and LC3B, increased the survival time, and decreased the tumor volume (P < 0.05). Our findings indicated that magnetochemotherapy (MHC) was substantially more effective than hyperthermia and/or chemotherapy alone. From a translational standpoint, the 5-Fu/MNPs-Fa would be a promising candidate sustained drug targeting system that could improve cancer cell therapy via inducing apoptosis and autophagy.
Graphical Abstract
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Xiang J, Gong W, Liu J, Zhang H, Li M, Wang R, Lv Y, Sun P. Identification of DLL3-related genes affecting the prognosis of patients with colon adenocarcinoma. Front Genet 2023; 14:1098190. [PMID: 37274780 PMCID: PMC10233108 DOI: 10.3389/fgene.2023.1098190] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 04/24/2023] [Indexed: 06/07/2023] Open
Abstract
Background: Delta-like ligand 3 (DLL3) is one of the NOTCH family of ligands, which plays a pro- or anti-carcinogenic role in some cancers. But the role of DLL3 in colon adenocarcinoma (COAD) has not been studied in depth. Materials and methods: First, we used Kaplan-Meier (K-M) curve to evaluate the effect of DLL3 on the prognosis of COAD in The Cancer Genome Atlas (TCGA), which was further validated in clinical samples for immunohistochemistry. Then we screened for differentially expressed genes (DEGs) of DLL3 by analyzing datasets of COAD samples from Gene Expression Omnibus (GEO) and TCGA. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and Gene Set Enrichment Analysis (GSEA) were conducted to explore the underlying mechanisms of DLL3-related in the development and prognosis of COAD. On the basis of DLL3-related signature genes, a prognostic model and a nomogram were constructed. Finally, CIBERSORT was applied to assess the proportion of immune cell types in COAD sample. Results: Survival analysis showed a significant difference in overall survival between high- and low-expression group (p = 0.0092), with COAD patients in the high-group having poorer 5-year survival rate. Gene functional enrichment analysis revealed that DLL3-related DEGs were mainly enriched in tumor- and immunity-related signaling pathways, containing AMPK pathway and mitophagy-animal. The comparison of COAD tumor and normal, DLL3 high- and low-expression groups by GSEA found that AMPK signaling pathway and mitophagy-animal were inhibited. Nomogram constructed from DLL3-related signature genes had a good predictive effect on the prognosis of COAD. We found the highest correlation between DLL3 and interstitial dendritic cell (iDC), natural killer (NK) cell and Interstitial dendritic cell (Tem). DLL3 was also revealed to be diagnostic for COAD. In clinical sample, we identified higher DLL3 expression in colon cancer tissue than in adjacent control (p < 0.0001) and in metastasis than in primary lesion (p = 0.0056). DLL3 expression was associated with stage and high DLL3 expression was observed to predict poorer overall survival (p = 0.004). Conclusion: It suggested that DLL3 may offer prognostic value and therapeutic potential for individualized treatment of COAD, and that it may has a diagnostic role in COAD.
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Affiliation(s)
- Jinyu Xiang
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Wenjing Gong
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Jiannan Liu
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Huijuan Zhang
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Ming Li
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Rujian Wang
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Yaodong Lv
- Departments of Neurology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Ping Sun
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
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Kasprzak A. Autophagy and the Insulin-like Growth Factor (IGF) System in Colonic Cells: Implications for Colorectal Neoplasia. Int J Mol Sci 2023; 24:ijms24043665. [PMID: 36835075 PMCID: PMC9959216 DOI: 10.3390/ijms24043665] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/02/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human malignancies worldwide. Along with apoptosis and inflammation, autophagy is one of three important mechanisms in CRC. The presence of autophagy/mitophagy in most normal mature intestinal epithelial cells has been confirmed, where it has mainly protective functions against reactive oxygen species (ROS)-induced DNA and protein damage. Autophagy regulates cell proliferation, metabolism, differentiation, secretion of mucins and/or anti-microbial peptides. Abnormal autophagy in intestinal epithelial cells leads to dysbiosis, a decline in local immunity and a decrease in cell secretory function. The insulin-like growth factor (IGF) signaling pathway plays an important role in colorectal carcinogenesis. This is evidenced by the biological activities of IGFs (IGF-1 and IGF-2), IGF-1 receptor type 1 (IGF-1R) and IGF-binding proteins (IGF BPs), which have been reported to regulate cell survival, proliferation, differentiation and apoptosis. Defects in autophagy are found in patients with metabolic syndrome (MetS), inflammatory bowel diseases (IBD) and CRC. In neoplastic cells, the IGF system modulates the autophagy process bidirectionally. In the current era of improving CRC therapies, it seems important to investigate the exact mechanisms not only of apoptosis, but also of autophagy in different populations of tumor microenvironment (TME) cells. The role of the IGF system in autophagy in normal as well as transformed colorectal cells still seems poorly understood. Hence, the aim of the review was to summarize the latest knowledge on the role of the IGF system in the molecular mechanisms of autophagy in the normal colon mucosa and in CRC, taking into account the cellular heterogeneity of the colonic and rectal epithelium.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland
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21
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Ahmadi-Dehlaghi F, Mohammadi P, Valipour E, Pournaghi P, Kiani S, Mansouri K. Autophagy: A challengeable paradox in cancer treatment. Cancer Med 2023. [PMID: 36760166 DOI: 10.1002/cam4.5577] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/14/2022] [Accepted: 12/21/2022] [Indexed: 02/11/2023] Open
Abstract
OBJECTIVE Autophagy is an intracellular degradation pathway conserved in all eukaryotes from yeast to humans. This process plays a quality-control role by destroying harmful cellular components under normal conditions, maintaining cell survival, and establishing cellular adaptation under stressful conditions. Hence, there are various studies indicating dysfunctional autophagy as a factor involved in the development and progression of various human diseases, including cancer. In addition, the importance of autophagy in the development of cancer has been highlighted by paradoxical roles, as a cytoprotective and cytotoxic mechanism. Despite extensive research in the field of cancer, there are many questions and challenges about the roles and effects suggested for autophagy in cancer treatment. The aim of this study was to provide an overview of the paradoxical roles of autophagy in different tumors and related cancer treatment options. METHODS In this study, to find articles, a search was made in PubMed and Google scholar databases with the keywords Autophagy, Autophagy in Cancer Management, and Drug Design. RESULTS According to the investigation, some studies suggest that several advanced cancers are dependent on autophagy for cell survival, so when cancer cells are exposed to therapy, autophagy is induced and suppresses the anti-cancer effects of therapeutic agents and also results in cell resistance. However, enhanced autophagy from using anti-cancer drugs causes autophagy-mediated cell death in several cancers. Because autophagy also plays roles in both tumor suppression and promotion further research is needed to determine the precise mechanism of this process in cancer treatment. CONCLUSION We concluded in this article, autophagy manipulation may either promote or hinder the growth and development of cancer according to the origin of the cancer cells, the type of cancer, and the behavior of the cancer cells exposed to treatment. Thus, before starting treatment it is necessary to determine the basal levels of autophagy in various cancers.
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Affiliation(s)
- Farnaz Ahmadi-Dehlaghi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Biology, Payame Noor University, Tehran, Iran
| | - Parisa Mohammadi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Elahe Valipour
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Sarah Kiani
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
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22
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Xie H, Qiang P, Wang Y, Xia F, Liu P, Li M. Discovery and mechanism studies of a novel ATG4B inhibitor Ebselen by drug repurposing and its anti-colorectal cancer effects in mice. Cell Biosci 2022; 12:206. [PMID: 36539845 PMCID: PMC9767854 DOI: 10.1186/s13578-022-00944-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Cysteine protease ATG4B, a key autophagy protein, is an attractive target for colorectal cancer therapy. However, ATG4B inhibitors with higher efficiency, safety, and clear mechanism are still limited. In this study, we discovered ATG4B inhibitors based on the FDA-approved drug library through FRET-based high-throughput screening and gel-based analysis. Among the nine hits, compound Ebselen showed the most potent ATG4B inhibitory activity (IC50 = 189 nM) and exhibited controllable selectivity and structural optimizable possibility against ATG4A and caspases. We then performed mass spectrometry assay and cysteine mutations to confirm that Ebselen could covalently bind to ATG4B at Cys74. Moreover, Cys292 and Cys361 instead of Cys74 are responsible for the redox-oligomerization and efficient activity inhibition of ATG4B. Ultimately through cell culture and mouse xenograft tumor models, we established the impact of Ebselen on autophagy and tumor suppression via ATG4B inhibition other than apoptosis. These results suggest that old drug Ebselen as an ATG4B inhibitor through oxidative modification may be repurposed as a promising anti-colorectal cancer drug.
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Affiliation(s)
- Huazhong Xie
- grid.12981.330000 0001 2360 039XSchool of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006 Guangdong China
| | - Pengfei Qiang
- grid.12981.330000 0001 2360 039XSchool of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006 Guangdong China
| | - Yao Wang
- grid.12981.330000 0001 2360 039XSchool of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006 Guangdong China
| | - Fan Xia
- grid.12981.330000 0001 2360 039XSchool of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006 Guangdong China
| | - Peiqing Liu
- grid.12981.330000 0001 2360 039XSchool of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006 Guangdong China
| | - Min Li
- grid.12981.330000 0001 2360 039XSchool of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006 Guangdong China
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23
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Jang WY, Kim MY, Cho JY. Antioxidant, Anti-Inflammatory, Anti-Menopausal, and Anti-Cancer Effects of Lignans and Their Metabolites. Int J Mol Sci 2022; 23:ijms232415482. [PMID: 36555124 PMCID: PMC9778916 DOI: 10.3390/ijms232415482] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/01/2022] [Accepted: 12/04/2022] [Indexed: 12/12/2022] Open
Abstract
Since chronic inflammation can be seen in severe, long-lasting diseases such as cancer, there is a high demand for effective methods to modulate inflammatory responses. Among many therapeutic candidates, lignans, absorbed from various plant sources, represent a type of phytoestrogen classified into secoisolariciresionol (Seco), pinoresinol (Pino), matairesinol (Mat), medioresinol (Med), sesamin (Ses), syringaresinol (Syr), and lariciresinol (Lari). Lignans consumed by humans can be further modified into END or ENL by the activities of gut microbiota. Lignans are known to exert antioxidant and anti-inflammatory activities, together with activity in estrogen receptor-dependent pathways. Lignans may have therapeutic potential for postmenopausal symptoms, including cardiovascular disease, osteoporosis, and psychological disorders. Moreover, the antitumor efficacy of lignans has been demonstrated in various cancer cell lines, including hormone-dependent breast cancer and prostate cancer, as well as colorectal cancer. Interestingly, the molecular mechanisms of lignans in these diseases involve the inhibition of inflammatory signals, including the nuclear factor (NF)-κB pathway. Therefore, we summarize the recent in vitro and in vivo studies evaluating the biological effects of various lignans, focusing on their values as effective anti-inflammatory agents.
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Affiliation(s)
- Won Young Jang
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Mi-Yeon Kim
- School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea
- Correspondence: (M.-Y.K.); (J.Y.C.); Tel.: +82-2-820-0458 (M.-Y.K.); +82-31-290-7868 (J.Y.C.)
| | - Jae Youl Cho
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Republic of Korea
- Correspondence: (M.-Y.K.); (J.Y.C.); Tel.: +82-2-820-0458 (M.-Y.K.); +82-31-290-7868 (J.Y.C.)
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24
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Yu L, Zhang MM, Hou JG. Molecular and cellular pathways in colorectal cancer: apoptosis, autophagy and inflammation as key players. Scand J Gastroenterol 2022; 57:1279-1290. [PMID: 35732586 DOI: 10.1080/00365521.2022.2088247] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colorectal carcinogenesis (CRC) is one of the most aggressive forms of cancer, particularly in developing countries. It accounts for the second and third-highest reason for cancer-induced lethality in women and men respectively. CRC involves genetic and epigenetic modifications in colonic epithelium, leading to colon adenocarcinoma. The current review highlights the pathogenic mechanisms and multifactorial etiology of CRC, influenced by apoptosis, inflammation, and autophagy pathways. METHODS We have carried out a selective literature review on mechanisms contributing to the pathogenesis of CRC. RESULTS Resistance to senescence and apoptosis of the mesenchymal cells, which play a key role in intestinal organogenesis, morphogenesis and homeostasis, appears important for sporadic CRC. Additionally, inflammation-associated tumorigenesis is a key incident in CRC, supported by immune disruptors, adaptive and innate immune traits, environmental factors, etc. involving oxidative stress, DNA damage and epigenetic modulations. The self-digesting mechanism, autophagy, also plays a twin role in CRC through the participation of LC3/LC3-II, Beclin-1, ATG5, other autophagy proteins, and Inflammatory Bowel Disease (IBD) susceptibility genes. It facilitates the promotion of effective surveillance pathways and stimulates the generation of malignant tumor cells. The autophagy and apoptotic pathways undergo synergistic or antagonistic interactions in CRC and bear a critical association with IBD that results from the pro-neoplastic effects of persistent intestinal inflammation. Conversely, pro-inflammatory factors stimulate tumor growth and angiogenesis and inhibit apoptosis, suppressing anti-tumor activities. CONCLUSION Hence, research attempts for the development of potential therapies for CRC are in progress, primarily based on combinatorial approaches targeting apoptosis, inflammation, and autophagy.
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Affiliation(s)
- Lei Yu
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Miao-Miao Zhang
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Ji-Guang Hou
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
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25
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Hu D, Huo Y, Xue Y, Feng H, Sun W, Wang H, Wu J, Wang X. Clinical application of autophagy proteins as prognostic biomarkers in colorectal cancer: a meta-analysis. Future Oncol 2022; 18:3537-3549. [PMID: 36189673 DOI: 10.2217/fon-2022-0458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Aim: To evaluate the prognostic value of autophagy proteins in colorectal cancer (CRC). Methods: Six potential autophagy proteins were analyzed (Beclin-1, LC3A, LC3B, ULK1, ATG10 and p62). Hazard ratios (HRs) and 95% CIs for overall survival (OS) of CRC patients were calculated. Results: A total of 20 studies were included. High expression of LC3B and p62 was associated with favorable OS (HR: 0.56, 95% CI: 0.40-0.80; HR: 0.76, 95% CI: 0.61-0.96), whereas high expression of Beclin-1 (HR: 1.47, 95% CI: 1.05-2.06) and ULK1 (HR: 1.92. 95% CI: 1.05-3.53) might predict worse OS in CRC patients. Conclusion: Beclin-1, LC3B and p62 might act as promising prognostic biomarkers for CRC. High LC3 and p62 expression can be reliable tools for metastasis prediction.
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Affiliation(s)
- Dongqing Hu
- Department of Healthcare Security Management, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China.,Tibetan Medicine Administration of Tibet Autonomous Region, Chengguan District, Lhasa, China.,Department of Digestive Endoscopy, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 42, Wenhua West Road, Jinan, Shandong Province, 250011, China
| | - Yanming Huo
- Cardiovascular Medicine Department, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China
| | - Ye Xue
- Department of Digestive Endoscopy, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 42, Wenhua West Road, Jinan, Shandong Province, 250011, China
| | - Haixia Feng
- Department of Infection Management, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 42, Wenhua West Road, Jinan, Shandong Province, 250011, China
| | - Wei Sun
- Cardiovascular Medicine Department, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China
| | - Huiqi Wang
- Cardiovascular Medicine Department, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China
| | - Jing Wu
- Cardiovascular Medicine Department, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China
| | - Xiaoyan Wang
- Department of Healthcare Security Management, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6, Huajiadi Road, Chaoyang District, Beijing, 100102, China.,Tibetan Medicine Administration of Tibet Autonomous Region, Chengguan District, Lhasa, China
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26
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Nuclear Beclin 1 Destabilizes Retinoblastoma Protein to Promote Cell Cycle Progression and Colorectal Cancer Growth. Cancers (Basel) 2022; 14:cancers14194735. [PMID: 36230664 PMCID: PMC9563141 DOI: 10.3390/cancers14194735] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/11/2022] [Accepted: 09/16/2022] [Indexed: 11/29/2022] Open
Abstract
Simple Summary The role of autophagy core-protein Beclin 1 in colorectal cancer (CRC) development remains controversial. Here, we show that nuclear Beclin 1 is up-regulated in CRC with a negative correlation to RB protein expression. Silencing of BECN1 up-regulates RB expression resulting in cell cycle G1 arrest and inhibition of xenograft tumor growth independent of p53. Ablation of BECN1 facilitates MDM2–MDMX complex formation to promote MDMX polyubiquitination and degradation, consequently leading to RB protein stabilization. These results reveal that nuclear Beclin 1 can promote CRC growth through modulation of RB protein stability and imply that nuclear Beclin 1 may be a prognostic indicator in human colorectal cancer. Abstract Autophagy is elevated in colorectal cancer (CRC) and is generally associated with poor prognosis. However, the role of autophagy core-protein Beclin 1 remains controversial in CRC development. Here, we show that the expression of nuclear Beclin 1 protein is upregulated in CRC with a negative correlation to retinoblastoma (RB) protein expression. Silencing of BECN1 upregulates RB resulting in cell cycle G1 arrest and growth inhibition of CRC cells independent of p53. Furthermore, ablation of BECN1 inhibits xenograft tumor growth through elevated RB expression and reduced autophagy, while simultaneous silencing of RB1 restores tumor growth but has little effect on autophagy. Mechanistically, knockdown of BECN1 promotes the complex formation of MDM2 and MDMX, resulting in MDM2-dependent MDMX instability and RB stabilization. Our results demonstrate that nuclear Beclin 1 can promote cell cycle progression through modulation of the MDM2/X-RB pathway and suggest that Beclin 1 promotes CRC development by facilitating both cell cycle progression and autophagy.
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27
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Mahgoub E, Taneera J, Sulaiman N, Saber-Ayad M. The role of autophagy in colorectal cancer: Impact on pathogenesis and implications in therapy. Front Med (Lausanne) 2022; 9:959348. [PMID: 36160153 PMCID: PMC9490268 DOI: 10.3389/fmed.2022.959348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/11/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is considered as a global major cause of cancer death. Surgical resection is the main line of treatment; however, chemo-, radiotherapy and other adjuvant agents are crucial to achieve good outcomes. The tumor microenvironment (TME) is a well-recognized key player in CRC progression, yet the processes linking the cancer cells to its TME are not fully delineated. Autophagy is one of such processes, with a controversial role in the pathogenesis of CRC, with its intricate links to many pathological factors and processes. Autophagy may apparently play conflicting roles in carcinogenesis, but the precise mechanisms determining the overall direction of the process seem to depend on the context. Additionally, it has been established that autophagy has a remarkable effect on the endothelial cells in the TME, the key substrate for angiogenesis that supports tumor metastasis. Favorable response to immunotherapy occurs only in a specific subpopulation of CRC patients, namely the microsatellite instability-high (MSI-H). In view of such limitations of immunotherapy in CRC, modulation of autophagy represents a potential adjuvant strategy to enhance the effect of those relatively safe agents on wider CRC molecular subtypes. In this review, we discussed the molecular control of autophagy in CRC and how autophagy affects different processes and mechanisms that shape the TME. We explored how autophagy contributes to CRC initiation and progression, and how it interacts with tumor immunity, hypoxia, and oxidative stress. The crosstalk between autophagy and the TME in CRC was extensively dissected. Finally, we reported the clinical efforts and challenges in combining autophagy modulators with various cancer-targeted agents to improve CRC patients’ survival and restrain cancer growth.
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Affiliation(s)
- Eglal Mahgoub
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Jalal Taneera
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Nabil Sulaiman
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Maha Saber-Ayad
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Faculty of Medicine, Cairo University, Giza, Egypt
- *Correspondence: Maha Saber-Ayad,
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28
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Duan L, Xia Y, Li C, Lan N, Hou X. Identification of Autophagy-Related LncRNA to Predict the Prognosis of Colorectal Cancer. Front Genet 2022; 13:906900. [PMID: 36035142 PMCID: PMC9403719 DOI: 10.3389/fgene.2022.906900] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 06/17/2022] [Indexed: 11/18/2022] Open
Abstract
Objective: To establish a prediction model based on autophagy-related lncRNAs and investigate the functional enrichment of autophagy-related lncRNAs in colorectal cancer. Methods: TCGA database was used to extract the transcriptome data and clinical features of colorectal cancer patients. HADb was used to obtain autophagy-related genes. Pearson correlation analysis was performed to identify autophagy-related lncRNAs. The autophagy-related lncRNAs with prognostic values were selected. Based on the selected lncRNAs, the risk score model and nomogram were constructed, respectively. Calibration curve, concordance index, and ROC curve were performed to evaluate the predictive efficacy of the prediction model. GSEA was performed to figure out the functional enrichment of autophagy-related lncRNAs. Results: A total of 13413 lncRNAs and 938 autophagy-related genes were obtained. A total of 709 autophagy-related genes were identified in colon cancer tissues, and 11 autophagy-related lncRNAs (AL138756.1, LINC01063, CD27-AS1, LINC00957, EIF3J-DT, LINC02474, SNHG16, AC105219.1, AC068580.3, LINC02381, and LINC01011) were finally selected and set as prognosis-related lncRNAs. According to the risk score, patients were divided into the high-risk and low-risk groups, respectively. The survival K–M (Kaplan–Meier) curve showed the low-risk group exhibits better overall survival than the high-risk group. The AUCs under the ROC curves were 0.72, 0.814, and 0.83 at 1, 3, and 5 years, respectively. The C-index (concordance index) of the model was 0.814. The calibration curves at 1, 3, and 5 years showed the predicting values were consistent with the actual values. Functional enrichment analysis showed that autophagy-related lncRNAs were enriched in several pathways. Conclusions: A total of 11 specific autophagy-related lncRNAs were identified to own prognostic value in colon cancer. The predicting model based on the lncRNAs and clinical features can effectively predict the OS. Furthermore, functional enrichment analysis showed that autophagy-related genes were enriched in various biological pathways.
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Affiliation(s)
- Ling Duan
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Yang Xia
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Oncology, The First People’s Hospital of Lanzhou, Lanzhou, China
| | - Chunmei Li
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Ning Lan
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Xiaoming Hou
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- *Correspondence: Xiaoming Hou,
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29
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Manzoor S, Muhammad JS, Maghazachi AA, Hamid Q. Autophagy: A Versatile Player in the Progression of Colorectal Cancer and Drug Resistance. Front Oncol 2022; 12:924290. [PMID: 35912261 PMCID: PMC9329589 DOI: 10.3389/fonc.2022.924290] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is among the topmost malignancies for both genders. Despite the high incidence rate and advances in diagnostic tools, treatment in many cases is still ineffective. Most cancerous lesions in CRC begin as benign, followed by the development of invasive forms and metastases. The development of CRC has been linked to defects in autophagy, which plays both a pro-and anti-tumor role and is mainly context-dependent. Autophagy suppression could enhance apoptosis via p53 activation, or autophagy also promotes tumor progression by maintaining tumor growth and increasing resistance to chemotherapy. Autophagy promotes the invasion and metastasis of CRC cells via increased epithelial-mesenchymal transition (EMT). Moreover, dysbiosis of gut microbiota upregulated autophagy and metastasis markers. Autophagy responses may also modulate the tumor microenvironment (TME) via regulating the differentiation process of several innate immune cells. Treatments that promote tumor cell death by stimulating or inhibiting autophagy could be beneficial if used as an adjunct treatment, but the precise role of various autophagy-modulating drugs in CRC patients is needed to be explored. In this article, we present an overview of the autophagy process and its role in the pathogenesis and therapeutic resistance of CRC. Also, we focused on the current understanding of the role of the EMT and TME, including its relation to gut microbiota and immune cells, in autophagic manipulation of CRC. We believe that there is a potential link between autophagy, TME, EMT, and drug resistance, suggesting that further studies are needed to explore this aspect.
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Affiliation(s)
- Shaista Manzoor
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Azzam A. Maghazachi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Qutayba Hamid
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, QC, Canada
- *Correspondence: Qutayba Hamid,
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30
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High Expression of a tRNAPro Derivative Associates with Poor Survival and Independently Predicts Colorectal Cancer Recurrence. Biomedicines 2022; 10:biomedicines10051120. [PMID: 35625858 PMCID: PMC9138872 DOI: 10.3390/biomedicines10051120] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/03/2022] [Accepted: 05/10/2022] [Indexed: 12/29/2022] Open
Abstract
Colorectal cancer (CRC) is the second most lethal cause of cancer-related deaths in Europe. Fragments of tRNAPro are conserved among vertebrates, characterized by pleiotropic regulatory functions and have been found to discriminate colorectal tumors from normal colorectal mucosa. In the current study, we investigated the prognostic utility of 5′-tiRNA-ProTGG levels in CRC. For this purpose, total RNA was extracted from 155 malignant colorectal tumors and 74 adjacent non-cancerous tissue specimens, polyadenylated and reverse-transcribed using an oligo-dT adapter as primer. Real-time quantitative PCR (qPCR) was used to assess the levels of 5′-tiRNA-ProTGG. Kaplan-Meier survival analysis demonstrated that high 5′-tiRNA-ProTGG levels predict both poor disease-free survival (DFS) and overall survival (OS) of CRC patients. Of note, high 5′-tiRNA-ProTGG levels retain their unfavorable prognostic value in patients with rectal cancer and/or moderately differentiated CRC (grade II). More importantly, multivariate cox regression analysis highlighted that the overexpression of 5′-tiRNA-ProTGG constitutes an adverse prognostic factor predicting short-term relapse of CRC patients independently of the established prognosticators in CRC. Finally, bioinformatics analysis unveiled a potentially critical role of 5′-tiRNA-ProTGG regarding the maintenance of cellular homeostasis, signaling, cell communication, and cellular motility.
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31
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El Zarif T, Yibirin M, De Oliveira-Gomes D, Machaalani M, Nawfal R, Bittar G, Bahmad HF, Bitar N. Overcoming Therapy Resistance in Colon Cancer by Drug Repurposing. Cancers (Basel) 2022; 14:cancers14092105. [PMID: 35565237 PMCID: PMC9099737 DOI: 10.3390/cancers14092105] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Despite improvements in standardized screening methods and the development of promising therapies for colorectal cancer (CRC), survival rates are still low. Drug repurposing offers an affordable solution to achieve new indications for previously approved drugs that could play a protagonist or adjuvant role in the treatment of CRC. In this review, we summarize the current data supporting drug repurposing as a feasible option for patients with CRC. Abstract Colorectal cancer (CRC) is the third most common cancer in the world. Despite improvement in standardized screening methods and the development of promising therapies, the 5-year survival rates are as low as 10% in the metastatic setting. The increasing life expectancy of the general population, higher rates of obesity, poor diet, and comorbidities contribute to the increasing trends in incidence. Drug repurposing offers an affordable solution to achieve new indications for previously approved drugs that could play a protagonist or adjuvant role in the treatment of CRC with the advantage of treating underlying comorbidities and decreasing chemotherapy toxicity. This review elaborates on the current data that supports drug repurposing as a feasible option for patients with CRC with a focus on the evidence and mechanism of action promising repurposed candidates that are widely used, including but not limited to anti-malarial, anti-helminthic, anti-inflammatory, anti-hypertensive, anti-hyperlipidemic, and anti-diabetic agents.
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Affiliation(s)
- Talal El Zarif
- Faculty of Medicine, Lebanese University, Beirut 1003, Lebanon; (T.E.Z.); (M.M.); (R.N.)
| | - Marcel Yibirin
- Internal Medicine Residency Program, Department of Medicine, Boston University Medical Center, Boston, MA 02218, USA;
| | - Diana De Oliveira-Gomes
- Department of Research, Foundation for Clinic, Public Health, and Epidemiological Research of Venezuela (FISPEVEN), Caracas 1050, Venezuela;
| | - Marc Machaalani
- Faculty of Medicine, Lebanese University, Beirut 1003, Lebanon; (T.E.Z.); (M.M.); (R.N.)
| | - Rashad Nawfal
- Faculty of Medicine, Lebanese University, Beirut 1003, Lebanon; (T.E.Z.); (M.M.); (R.N.)
| | | | - Hisham F. Bahmad
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
- Correspondence: ; Tel.: +1-786-961-0216
| | - Nizar Bitar
- Head of Hematology-Oncology Division, Sahel General Hospital, Beirut 1002, Lebanon;
- President of the Lebanese Society of Medical Oncology (LSMO), Beirut 1003, Lebanon
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3,4-Dihydroxyphenylethanol (DPE or Hydroxytyrosol) Counteracts ERK1/2 and mTOR Activation, Pro-Inflammatory Cytokine Release, Autophagy and Mitophagy Reduction Mediated by Benzo[a]pyrene in Primary Human Colonic Epithelial Cells. Pharmaceutics 2022; 14:pharmaceutics14030663. [PMID: 35336037 PMCID: PMC8948646 DOI: 10.3390/pharmaceutics14030663] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/10/2022] [Accepted: 03/16/2022] [Indexed: 02/04/2023] Open
Abstract
Understanding the effects induced by carcinogens on primary colonic epithelial cells and how to counteract them might help to prevent colon cancer, which is one of the most frequent and aggressive cancers. In this study, we exposed primary human colonic epithelial cells (HCoEpC) to Benzo[a]pyrene (B[a]P) and found that it led to an increased production of pro-inflammatory cytokines and activated ERK1/2 and mTOR. These pathways are known to be involved in inflammatory bowel disease (IBD), which represents a colon cancer risk factor. Moreover, B[a]P reduced autophagy and mitophagy, processes whose dysregulation has been clearly demonstrated to predispose to cancer either by in vitro or in vivo studies. Interestingly, all the effects induced by B[a]P could be counteracted by 3,4-Dihydroxyphenylethanol (DPE or Hydroxytyrosol, H), the most powerful anti-inflammatory and antioxidant compound contained in olive oil. This study sheds light on the mechanisms that could be involved in colon carcinogenesis induced by a chemical carcinogen and identifies a safe natural product that may help to prevent them.
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Bueno-Martínez E, Lara-Almunia M, Rodríguez-Arias C, Otero-Rodríguez A, Garfias-Arjona S, González-Sarmiento R. Polymorphisms in autophagy genes are genetic susceptibility factors in glioblastoma development. BMC Cancer 2022; 22:146. [PMID: 35123435 PMCID: PMC8818195 DOI: 10.1186/s12885-022-09214-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 01/19/2022] [Indexed: 12/31/2022] Open
Abstract
Background Glioblastoma is the most aggressive and common malignant primary brain tumor in adults. Many genetic, epigenetic and genomic mutations have been identified in this tumor, but no driving cause has been identified yet for glioblastoma pathogenesis. Autophagy has proved to be deregulated in different diseases such as cancer where it has a dual role, acting as a tumor suppression mechanism during the first steps of tumor development and promoting cancer cells survival in stablished tumors. Methods Here, we aimed to assess the potential association between several candidate polymorphisms in autophagy genes (ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183, ATG5 rs2245214, NOD2 rs2066844 and rs2066845) and glioblastoma susceptibility. Results Our results showed a significant correlation between ATG2B rs3759601, ATG10 rs1864183 and NOD2 rs2066844 variants and higher risk to suffer glioblastoma. In addition, the relationship between the different clinical features listed in glioblastoma patients and candidate gene polymorphisms was also investigated, finding that ATG10 rs1864183 might be a promising prognosis factor for this tumor. Conclusions This is the first report evaluating the role of different variants in autophagy genes in modulating glioblastoma risk and our results emphasize the importance of autophagy in glioblastoma development. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09214-y.
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Jamali L, Sadeghi H, Ghasemi MR, Mohseni R, Nazemalhosseini-Mojarad E, Yassaee VR, Larki P, Zali MR, Mirfakhraie R. Autophagy ATG16L1 rs2241880 impacts the colorectal cancer risk: A case-control study. J Clin Lab Anal 2021; 36:e24169. [PMID: 34894411 PMCID: PMC8761398 DOI: 10.1002/jcla.24169] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 11/29/2022] Open
Abstract
Background Despite many efforts to discover the important role of the autophagy process in the pathogenesis of colorectal cancer (CRC), the exact involved molecular mechanism still remains to be elucidated. Recently, a limited number of studies have been employed to discover the impact of autophagy genes’ variants on the development and progression of CRC. Here, we evaluated the association between two single‐nucleotide polymorphisms (SNPs) in the main components of the autophagy genes, ATG16L1 rs2241880, and ATG5 rs1475270, and the CRC risk in an Iranian population. Methods During this investigation, a total of 369 subjects, including 179 CRC patients and 190 non‐cancer controls have been genotyped using Tetra‐primer amplification refractory mutation system‐polymerase chain reaction (TP‐ARMS‐PCR) method. Result The results demonstrated that the T allele of the ATG16L1 rs2241880 was significantly associated with the increased risk of CRC in the studied population (OR 1.64, 95% CI: 1.21–2.22, p = 0.0015). Moreover, ATG16L1 rs2241880 TT genotype increased the susceptibility to CRC (OR 3.31, 95% CI: 1.64–6.69, p = 0.0008). Furthermore, a significant association was observed under the recessive and dominant inheritance models (p = 0.0015 and p = 0.017, respectively). No statistically significant differences were found in the ATG5 rs1475270 alleles and genotypes between the cases and controls. Conclusion The results of the present study may be helpful concerning the risk stratification in CRC patients based on the genotyping approach of autophagy pathways and emphasize the need for further investigations among different populations and ethnicities to refine our conclusions.
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Affiliation(s)
- Leila Jamali
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Sadeghi
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad-Reza Ghasemi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roohollah Mohseni
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Department of Gastrointestinal Cancer, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Reza Yassaee
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pegah Larki
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Department of Gastrointestinal Cancer, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Mirfakhraie
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Understanding the Role of Autophagy in Cancer Formation and Progression Is a Real Opportunity to Treat and Cure Human Cancers. Cancers (Basel) 2021; 13:cancers13225622. [PMID: 34830777 PMCID: PMC8616104 DOI: 10.3390/cancers13225622] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/02/2021] [Accepted: 11/08/2021] [Indexed: 01/18/2023] Open
Abstract
Simple Summary The modulation of autophagy represents a potential therapeutic strategy for cancer. More than one hundred clinical trials have been conducted or are ongoing to explore the efficacy of autophagy modulators to reduce the tumor growth and potentiate the anti-cancer effects of conventional therapy. Despite this, the effective role of autophagy during tumor initiation, growth, and metastasis remains not well understood. Depending on the cancer type and stage of cancer, autophagy may have tumor suppressor properties as well as help cancer cells to proliferate and evade cancer therapy. The current review aims to summarize the current knowledge about the autophagy implications in cancer and report the therapeutic opportunities based on the modulation of the autophagy process. Abstract The malignant transformation of a cell produces the accumulation of several cellular adaptions. These changes determine variations in biological processes that are necessary for a cancerous cell to survive during stressful conditions. Autophagy is the main nutrient recycling and metabolic adaptor mechanism in eukaryotic cells, represents a continuous source of energy and biomolecules, and is fundamental to preserve the correct cellular homeostasis during unfavorable conditions. In recent decades, several findings demonstrate a close relationship between autophagy, malignant transformation, and cancer progression. The evidence suggests that autophagy in the cancer context has a bipolar role (it may act as a tumor suppressor and as a mechanism of cell survival for established tumors) and demonstrates that the targeting of autophagy may represent novel therapeutic opportunities. Accordingly, the modulation of autophagy has important clinical benefits in patients affected by diverse cancer types. Currently, about 30 clinical trials are actively investigating the efficacy of autophagy modulators to enhance the efficacy of cytotoxic chemotherapy treatments. A deeper understanding of the molecular pathways regulating autophagy in the cancer context will provide new ways to target autophagy for improving the therapeutic benefits. Herein, we describe how autophagy participates during malignant transformation and cancer progression, and we report the ultimate efforts to translate this knowledge into specific therapeutic approaches to treat and cure human cancers.
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The gastrointestinal microbiota in colorectal cancer cell migration and invasion. Clin Exp Metastasis 2021; 38:495-510. [PMID: 34748126 DOI: 10.1007/s10585-021-10130-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023]
Abstract
Colorectal carcinoma is the third most common cancer in developed countries and the second leading cause of cancer-related mortality. Interest in the influence of the intestinal microbiota on CRC emerged rapidly in the past few years, and the close presence of microbiota to the tumour mass creates a unique microenvironment in CRC. The gastrointestinal microbiota secrete factors that can contribute to CRC metastasis by influencing, for example, epithelial-to-mesenchymal transition. Although the role of EMT in metastasis is well-studied, mechanisms by which gastrointestinal microbiota contribute to the progression of CRC remain poorly understood. In this review, we will explore bacterial factors that contribute to the migration and invasion of colorectal carcinoma and the mechanisms involved. Bacteria involved in the induction of metastasis in primary CRC include Fusobacterium nucleatum, Enterococcus faecalis, enterotoxigenic Bacteroides fragilis, Escherichia coli and Salmonella enterica. Examples of prominent bacterial factors secreted by these bacteria include Fusobacterium adhesin A and Bacteroides fragilis Toxin. Most of these factors induce EMT-like properties in carcinoma cells and, as such, contribute to disease progression by affecting cell-cell adhesion, breakdown of the extracellular matrix and reorganisation of the cytoskeleton. It is of utmost importance to elucidate how bacterial factors promote CRC recurrence and metastasis to increase patient survival. So far, mainly animal models have been used to demonstrate this interplay between the host and microbiota. More human-based models are needed to study the mechanisms that promote migration and invasion and mimic the progression and recurrence of CRC.
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Chen S, Wang Y, Wang B, Zhang L, Su Y, Xu M, Zhang M. A signature based on 11 autophagy genes for prognosis prediction of colorectal cancer. PLoS One 2021; 16:e0258741. [PMID: 34699544 PMCID: PMC8547631 DOI: 10.1371/journal.pone.0258741] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 10/04/2021] [Indexed: 01/26/2023] Open
Abstract
Aim To develop an autophagy-gene-based signature that could help to anticipate the therapeutic effects of Colorectal Cancer (CRC). Methods We downloaded the gene expression profiles of CRC samples from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. Genes with significant prognostic value in CRC were screened through univariate Cox regression analysis, while the LASSO Cox regression method was applied to screen optimal genes to construct the autophagy‐related prognostic signature. Results 11 autophagy genes were identified and selected for the establishment of prognosis prediction model for CRC patients. The CRC patients were classified into the low- and high-risk groups according to the optimal cutoff value. The time-dependent ROC curves indicated the good performance of this model in prognosis prediction, with AUC values of 0.66, 0.66, and 0.67 at 1, 3 and 5 years for TCGA samples, as well as AUC values of 0.63, 0.65 and 0.64 for GEO samples, respectively. The multivariate Cox regression analysis results confirmed risk score as the independent marker for prognosis prediction in CRC. Besides, the constructed nomogram also had high predictive value. The results analysis on the tumor infiltrating immune cells (TIICs) relative ratios and mRNA levels of key immune checkpoint receptors indicated the signature was closely related to immune microenvironment of CRC in the context of TIICs and immune checkpoint receptors’ mRNA level. The proportion of MSI-L + MSI-H in the high-risk group was higher than that in the low-risk group. Moreover, the tumor purity was evaluated by estimate function package suggested that lower tumor purity in CRC might lead to a poorer prognosis. Conclusion The autophagy-related features obtained in this study were able to divide the CRC patients into low- and high-risk groups, which should be contribute to the decision-making of CRC treatment.
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Affiliation(s)
- Shuo Chen
- Department of colorectal Surgery, Tianjin Union Medical Center, Tianjin, P.R. China
- Tianjin Institute of Coloproctology, Tianjin, P.R. China
- * E-mail:
| | - Yan Wang
- Department of Traditional Chinese Medicine, Shanghai Pudong New Area People’s Hospital, Shanghai, P.R. China
| | - Boxue Wang
- Department of colorectal Surgery, Tianjin Union Medical Center, Tianjin, P.R. China
- Tianjin Institute of Coloproctology, Tianjin, P.R. China
| | - Lin Zhang
- Department of colorectal Surgery, Tianjin Union Medical Center, Tianjin, P.R. China
- Tianjin Institute of Coloproctology, Tianjin, P.R. China
| | - Yinan Su
- Department of colorectal Surgery, Tianjin Union Medical Center, Tianjin, P.R. China
- Tianjin Institute of Coloproctology, Tianjin, P.R. China
| | - Mingyue Xu
- Department of colorectal Surgery, Tianjin Union Medical Center, Tianjin, P.R. China
- Tianjin Institute of Coloproctology, Tianjin, P.R. China
| | - Mingqing Zhang
- Department of colorectal Surgery, Tianjin Union Medical Center, Tianjin, P.R. China
- Tianjin Institute of Coloproctology, Tianjin, P.R. China
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Inoue T, Hayashi Y, Tsujii Y, Yoshii S, Sakatani A, Kimura K, Uema R, Kato M, Saiki H, Shinzaki S, Iijima H, Takehara T. Suppression of autophagy promotes fibroblast activation in p53-deficient colorectal cancer cells. Sci Rep 2021; 11:19524. [PMID: 34593902 PMCID: PMC8484348 DOI: 10.1038/s41598-021-98865-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 09/15/2021] [Indexed: 12/15/2022] Open
Abstract
Deficiency of p53 in cancer cells activates the transformation of normal tissue fibroblasts into carcinoma-associated fibroblasts; this promotes tumor progression through a variety of mechanisms in the tumor microenvironment. The role of autophagy in carcinoma-associated fibroblasts in tumor progression has not been elucidated. We aimed to clarify the significance of autophagy in fibroblasts, focusing on the TP53 status in co-cultured human colorectal cancer cell lines (TP53-wild-type colon cancer, HCT116; TP53-mutant colon cancer, HT29; fibroblast, CCD-18Co) in vitro. Autophagy in fibroblasts was significantly suppressed in association with ACTA2, CXCL12, TGFβ1, VEGFA, FGF2, and PDGFRA mRNA levels, when co-cultured with p53-deficient HCT116sh p53 cells. Exosomes isolated from the culture media of HCT116sh p53 cells significantly suppressed autophagy in fibroblasts via inhibition of ATG2B. Exosomes derived from TP53-mutant HT29 cells also suppressed autophagy in fibroblasts. miR-4534, extracted from the exosomes of HCT116sh p53 cells, suppressed ATG2B in fibroblasts. In conclusion, a loss of p53 function in colon cancer cells promotes the activation of surrounding fibroblasts through the suppression of autophagy. Exosomal miRNAs derived from cancer cells may play a pivotal role in the suppression of autophagy.
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Affiliation(s)
- Takanori Inoue
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yoshito Hayashi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yoshiki Tsujii
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Shunsuke Yoshii
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Akihiko Sakatani
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Keiichi Kimura
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryotaro Uema
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Minoru Kato
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hirotsugu Saiki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Shinichiro Shinzaki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hideki Iijima
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
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Melatonin Induces Autophagy via Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress Pathway in Colorectal Cancer Cells. Molecules 2021; 26:molecules26165038. [PMID: 34443626 PMCID: PMC8400139 DOI: 10.3390/molecules26165038] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 07/26/2021] [Accepted: 07/29/2021] [Indexed: 01/10/2023] Open
Abstract
Even though an increasing number of anticancer treatments have been discovered, the mortality rates of colorectal cancer (CRC) have still been high in the past few years. It has been discovered that melatonin has pro-apoptotic properties and counteracts inflammation, proliferation, angiogenesis, cell invasion, and cell migration. In previous studies, melatonin has been shown to have an anticancer effect in multiple tumors, including CRC, but the underlying mechanisms of melatonin action on CRC have not been fully explored. Thus, in this study, we investigated the role of autophagy pathways in CRC cells treated with melatonin. In vitro CRC cell models, HT-29, SW48, and Caco-2, were treated with melatonin. CRC cell death, oxidative stress, and autophagic vacuoles formation were induced by melatonin in a dose-dependent manner. Several autophagy pathways were examined, including the endoplasmic reticulum (ER) stress, 5′–adenosine monophosphate-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K), serine/threonine-specific protein kinase (Akt), and mammalian target of rapamycin (mTOR) signaling pathways. Our results showed that melatonin significantly induced autophagy via the ER stress pathway in CRC cells. In conclusion, melatonin demonstrated a potential as an anticancer drug for CRC.
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Thein W, Po WW, Choi WS, Sohn UD. Autophagy and Digestive Disorders: Advances in Understanding and Therapeutic Approaches. Biomol Ther (Seoul) 2021; 29:353-364. [PMID: 34127572 PMCID: PMC8255139 DOI: 10.4062/biomolther.2021.086] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/11/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022] Open
Abstract
The gastrointestinal (GI) tract is a series of hollow organs that is responsible for the digestion and absorption of ingested foods and the excretion of waste. Any changes in the GI tract can lead to GI disorders. GI disorders are highly prevalent in the population and account for substantial morbidity, mortality, and healthcare utilization. GI disorders can be functional, or organic with structural changes. Functional GI disorders include functional dyspepsia and irritable bowel syndrome. Organic GI disorders include inflammation of the GI tract due to chronic infection, drugs, trauma, and other causes. Recent studies have highlighted a new explanatory mechanism for GI disorders. It has been suggested that autophagy, an intracellular homeostatic mechanism, also plays an important role in the pathogenesis of GI disorders. Autophagy has three primary forms: macroautophagy, microautophagy, and chaperone-mediated autophagy. It may affect intestinal homeostasis, host defense against intestinal pathogens, regulation of the gut microbiota, and innate and adaptive immunity. Drugs targeting autophagy could, therefore, have therapeutic potential for treating GI disorders. In this review, we provide an overview of current understanding regarding the evidence for autophagy in GI diseases and updates on potential treatments, including drugs and complementary and alternative medicines.
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Affiliation(s)
- Wynn Thein
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Wah Wah Po
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Won Seok Choi
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Uy Dong Sohn
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
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Mani S, Swargiary G, Tyagi S, Singh M, Jha NK, Singh KK. Nanotherapeutic approaches to target mitochondria in cancer. Life Sci 2021; 281:119773. [PMID: 34192595 DOI: 10.1016/j.lfs.2021.119773] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 01/18/2023]
Abstract
Treatment of cancer cells exemplifies a difficult test in the light of challenges associated with the nature of cancer cells and the severe side effects too. After making a large number of trials using both traditional and advanced therapies (immunotherapy and hormone therapy), approaches to design new therapies have reached a saturation level. However, nanotechnology-based approaches exhibit higher efficacy and great potential to bypass many of such therapeutic limitations. Because of their higher target specificity, the use of nanoparticles offers incredible potential in cancer therapeutics. Mitochondria, acting as a factory of energy production in cells, reveal an important role in the death as well as the survival of cells. Because of its significant involvement in the proliferation of cancer cells, it is being regarded as an important target for cancer therapeutics. Numerous studies reveal that nanotechnology-based approaches to directly target the mitochondria may help in improving the survival rate of cancer patients. In the current study, we have detailed the significance of mitochondria in the development of cancer phenotype, as well as indicated it as the potential targets for cancer therapy. Our study further highlights the importance of different nanoparticle-based approaches to target mitochondria of cancer cells and the associated outcomes of different studies. Though, nanotechnology-based approaches to target mitochondria of cancer cells demonstrate a potential and efficient way in cancer therapeutics. Yet, further study is needed to overcome the linked limitations.
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Affiliation(s)
- Shalini Mani
- Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector 62, Noida, UP 201301, India.
| | - Geeta Swargiary
- Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector 62, Noida, UP 201301, India
| | - Sakshi Tyagi
- Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector 62, Noida, UP 201301, India
| | - Manisha Singh
- Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector 62, Noida, UP 201301, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida, Uttar Pradesh 201310, India
| | - Keshav K Singh
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
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Chaeichi-Tehrani N, Ferns GA, Hassanian SM, Khazaei M, Avan A. The Therapeutic Potential of Targeting Autophagy in The Treatment of Cancer. Curr Cancer Drug Targets 2021; 21:725-736. [PMID: 34077348 DOI: 10.2174/1568009621666210601113144] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 03/02/2021] [Accepted: 03/12/2021] [Indexed: 11/22/2022]
Abstract
Autophagy is a mechanism by which unwanted cellular components are degraded through a pathway that involves the lysosomes and contributes to several pathological conditions such as cancer. Gastrointestinal cancers affect the digestive organs from the esophagus to the anus and are among the most commonly diagnosed cancers globally. The modulation of autophagy using pharmacologic agents potentially offers a great potential for cancer therapy. In this review, some commonly used compounds, together with their molecular target and the mechanism through which they stimulate or block the autophagy pathway as well as their therapeutic benefit in treating patients with gastrointestinal cancers, are summarized.
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Affiliation(s)
- Negin Chaeichi-Tehrani
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
| | - Seyed Mahdi Hassanian
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic syndrome Research centre, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Autophagy Induction by Trichodermic Acid Attenuates Endoplasmic Reticulum Stress-Mediated Apoptosis in Colon Cancer Cells. Int J Mol Sci 2021; 22:ijms22115566. [PMID: 34070303 PMCID: PMC8197497 DOI: 10.3390/ijms22115566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/14/2021] [Accepted: 05/19/2021] [Indexed: 12/26/2022] Open
Abstract
Colorectal cancer (CRC) is the third leading malignant tumor in the world, which has high morbidity and mortality. In this study we found that trichodermic acid (TDA), a secondary metabolite isolated from the plant endophytic fungus Penicillium ochrochloronthe with a variety of biological and pharmacological activities, exhibited the antitumor effects on colorectal cancer cells in vitro and in vivo. Our results showed that TDA inhibited the proliferation of colon cancer cells in a dose-dependent manner. TDA induces sustained endoplasmic reticulum stress, which triggers apoptosis through IRE1α/XBP1 and PERK/ATF4/CHOP pathways. In addition, we found that TDA mediated endoplasmic reticulum stress also induces autophagy as a protective mechanism. Moreover, combined treatment of TDA with autophagy inhibitors significantly enhanced its anticancer effect. In conclusion, our results indicated that TDA can induce ER stress and autophagy mediated apoptosis, suggesting that targeting ER stress and autophagy may be an effective strategy for the treatment of CRC.
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Chen L, He M, Zhang M, Sun Q, Zeng S, Zhao H, Yang H, Liu M, Ren S, Meng X, Xu H. The Role of non-coding RNAs in colorectal cancer, with a focus on its autophagy. Pharmacol Ther 2021; 226:107868. [PMID: 33901505 DOI: 10.1016/j.pharmthera.2021.107868] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 04/16/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of malignant afflictions burdening people worldwide, mainly caused by shortages of effective medical intervention and poorly mechanistic understanding of the pathogenesis of CRC. Non-coding RNAs (ncRNAs) are a type of heterogeneous transcripts without the capability of coding protein, but have the potency of regulating protein-coding gene expression. Autophagy is an evolutionarily conserved catabolic process in which cytoplasmic contents are delivered to cellular lysosomes for degradation, resulting in the turnover of cellular components and producing energy for cell functions. A growing body of evidence reveals that ncRNAs, autophagy, and the crosstalks of ncRNAs and autophagy play intricate roles in the initiation, progression, metastasis, recurrence and therapeutic resistance of CRC, which confer ncRNAs and autophagy to serve as clinical biomarkers and therapeutic targets for CRC. In this review, we sought to delineate the complicated roles of ncRNAs, mainly including miRNAs, lncRNAs and circRNAs, in the pathogenesis of CRC, particularly focus on the regulatory role of ncRNAs in CRC-related autophagy, attempting to shed light on the complex pathological mechanisms, involving ncRNAs and autophagy, responsible for CRC tumorigenesis and development, so as to underpin the ncRNAs- and autophagy-based therapeutic strategies for CRC in clinical setting.
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Affiliation(s)
- Li Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Man He
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Meng Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qiang Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Sha Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Hui Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Han Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Maolun Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shan Ren
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xianli Meng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Haibo Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Li W, Liu C, Huang Z, Shi L, Zhong C, Zhou W, Meng P, Li Z, Wang S, Luo F, Yan J, Wu T. AKR1B10 negatively regulates autophagy through reducing GAPDH upon glucose starvation in colon cancer. J Cell Sci 2021; 134:237788. [PMID: 33758077 DOI: 10.1242/jcs.255273] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 03/12/2021] [Indexed: 12/17/2022] Open
Abstract
Autophagy is considered to be an important switch for facilitating normal to malignant cell transformation during colorectal cancer development. Consistent with other reports, we found that the membrane receptor Neuropilin1 (NRP1) is greatly upregulated in colon cancer cells that underwent autophagy upon glucose deprivation. However, the mechanism underlying NRP1 regulation of autophagy is unknown. We found that knockdown of NRP1 inhibits autophagy and largely upregulates the expression of aldo-keto reductase family 1 B10 (AKR1B10). Moreover, we demonstrated that AKR1B10 interacts with and inhibits the nuclear importation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and then subsequently represses autophagy. Interestingly, we also found that an NADPH-dependent reduction reaction could be induced when AKR1B10 interacts with GAPDH, and the reductase activity of AKR1B10 is important for its repression of autophagy. Together, our findings unravel a novel mechanism of NRP1 in regulating autophagy through AKR1B10.
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Affiliation(s)
- Wanyun Li
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361000, China
| | - Cong Liu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361000, China
| | - Zilan Huang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361000, China
| | - Lei Shi
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361000, China
| | - Chuanqi Zhong
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361000, China
| | - Wenwen Zhou
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361000, China
| | - Peipei Meng
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361000, China
| | - Zhenyu Li
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361000, China
| | - Shengyu Wang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361000, China
| | - Fanghong Luo
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361000, China
| | - Jianghua Yan
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361000, China
| | - Ting Wu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361000, China.,Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen 361000, China.,Xiamen University Research Center of Retroperitoneal Tumor Committee of Oncology Society of Chinese Medical Association, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361000, China.,Joint Laboratory of Xiamen University School of Medicine and Shanghai Jiangxia Blood Technology Co., Ltd., Xiamen 361000, China
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Lim SM, Mohamad Hanif EA, Chin SF. Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect. Cell Biosci 2021; 11:56. [PMID: 33743781 PMCID: PMC7981910 DOI: 10.1186/s13578-021-00570-z] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 03/08/2021] [Indexed: 02/07/2023] Open
Abstract
Autophagy is a conserved cellular process required to maintain homeostasis. The hallmark of autophagy is the formation of a phagophore that engulfs cytosolic materials for degradation and recycling to synthesize essential components. Basal autophagy is constitutively active under normal conditions and it could be further induced by physiological stimuli such as hypoxia, nutrient starvation, endoplasmic reticulum stress,energy depletion, hormonal stimulation and pharmacological treatment. In cancer, autophagy is highly context-specific depending on the cell type, tumour microenvironment, disease stage and external stimuli. Recently, the emerging role of autophagy as a double-edged sword in cancer has gained much attention. On one hand, autophagy suppresses malignant transformation by limiting the production of reactive oxygen species and DNA damage during tumour development. Subsequently, autophagy evolved to support the survival of cancer cells and promotes the tumourigenicity of cancer stem cells at established sites. Hence, autophagy is an attractive target for cancer therapeutics and researchers have been exploiting the use of autophagy modulators as adjuvant therapy. In this review, we present a summary of autophagy mechanism and controlling pathways, with emphasis on the dual-role of autophagy (double-edged sword) in cancer. This is followed by an overview of the autophagy modulation for cancer treatment and is concluded by a discussion on the current perspectives and future outlook of autophagy exploitation for precision medicine.
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Affiliation(s)
- Su Min Lim
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, W. Persekutuan, 56000, Kuala Lumpur, Malaysia
| | - Ezanee Azlina Mohamad Hanif
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, W. Persekutuan, 56000, Kuala Lumpur, Malaysia
| | - Siok-Fong Chin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, W. Persekutuan, 56000, Kuala Lumpur, Malaysia.
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Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts. Cancers (Basel) 2021; 13:cancers13061258. [PMID: 33809172 PMCID: PMC7998818 DOI: 10.3390/cancers13061258] [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: 02/04/2021] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary We investigated the influence of autophagy-related variants in modulating colorectal cancer (CRC) risk through a meta-analysis of genome-wide association study (GWAS) data from four large European cohorts. We found that genetic variants within the DAPK2 and ATG5 loci were associated with CRC risk. This study also shed some light onto the functional mechanisms behind the observed associations and demonstrated the impact of DAPK2rs11631973 and ATG5rs546456 polymorphisms on the modulation of host immune responses, blood derived-cell counts and serum inflammatory protein levels, which might be involved in promoting cancer development. No effect of the DAPK2 and ATG5 polymorphisms on the autophagy flux was observed. Abstract The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, DAPK2 (p = 2.19 × 10−5) and ATG5 (p = 6.28 × 10−4) were associated with the risk of CRC. Mechanistically, the DAPK2rs11631973G allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with Staphylococcus aureus (p = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (p = 0.0038) and serum levels of en-RAGE (p = 0.0068). ATG5rs546456T allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (p = 0.0088 and p = 0.0076, respectively), CD14+CD16− cell levels in blood (p = 0.0068) and serum levels of CCL19 and cortisol (p = 0.0052 and p = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the DAPK2 and ATG5 loci in the pathogenesis of CRC, likely through the modulation of host immune responses.
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Yang Y, Feng M, Bai L, Zhang M, Zhou K, Liao W, Lei W, Zhang N, Huang J, Li Q. The Effects of Autophagy-Related Genes and lncRNAs in Therapy and Prognosis of Colorectal Cancer. Front Oncol 2021; 11:582040. [PMID: 33777735 PMCID: PMC7991845 DOI: 10.3389/fonc.2021.582040] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 02/02/2021] [Indexed: 02/05/2023] Open
Abstract
Cellular autophagy plays an important role in the occurrence and development of colorectal cancer (CRC). Whether autophagy-related genes and lncRNAs can be used as ideal markers in CRC is still controversial. The purpose of this study is to identify novel treatment and prognosis markers of CRC. We downloaded transcription and clinical data of CRC from the GEO (GSE40967, GSE12954, GSE17536) and TCGA database, screened for differentially autophagy-related genes (DEAGs) and lncRNAs, constructed prognostic model, and analyzed its relationship with immune infiltration. TCGA and GEO datasets (GSE12954 and GSE17536) were used to validate the effect of the model. Oncomine database and Human Protein Atlas verified the expression of DEAGs. We obtained a total of 151 DEAGs in three verification sets collaboratively. Then we constructed a risk prognostic model through Lasso regression to obtain 15 prognostic DEAGs from the training set and verified the risk prognostic model in three verification sets. The low-risk group survived longer than the high-risk group. Age, gender, pathological stage, and TNM stage were related to the prognostic risk of CRC. On the other hand, BRAF status, RFS event, and tumor location are considered as most significant risk factors of CRC in the training set. Furthermore, we found that the immune score of the low-risk group was higher. The content of CD8 + T cells, active NK cells, macrophages M0, macrophages M1, and active dendritic cells was noted more in the high-risk group. The content of plasma cells, resting memory CD4 + T cells, resting NK cells, resting mast cells, and neutrophil cells was higher in the low-risk group. After all, the Oncomine database and immunohistochemistry verified that the expression level of most key autophagy-related genes was consistent with the results that we found. In addition, we obtained six lncRNAs co-expressed with DEAGs from the training set and found that the survival time was longer in the low-risk group. This finding was verified in the verification set and showed same trend to the results mentioned above. In the final analysis, these results indicate that autophagy-related genes and lncRNAs can be used as prognostic and therapeutic markers for CRC.
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Affiliation(s)
- Yang Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Sichuan, China.,West China Biomedical Big Data Center, Sichuan University, Sichuan, China
| | - Mingyang Feng
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Sichuan, China.,West China Biomedical Big Data Center, Sichuan University, Sichuan, China
| | - LiangLiang Bai
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Sichuan, China.,West China Biomedical Big Data Center, Sichuan University, Sichuan, China
| | - Mengxi Zhang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Sichuan, China.,West China Biomedical Big Data Center, Sichuan University, Sichuan, China
| | - Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Sichuan, China.,West China Biomedical Big Data Center, Sichuan University, Sichuan, China
| | - Weiting Liao
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Sichuan, China.,West China Biomedical Big Data Center, Sichuan University, Sichuan, China
| | - Wanting Lei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Sichuan, China.,West China Biomedical Big Data Center, Sichuan University, Sichuan, China
| | - Nan Zhang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Sichuan, China.,West China Biomedical Big Data Center, Sichuan University, Sichuan, China
| | - Jiaxing Huang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Sichuan, China.,West China Biomedical Big Data Center, Sichuan University, Sichuan, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Sichuan, China.,West China Biomedical Big Data Center, Sichuan University, Sichuan, China
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Ternet C, Kiel C. Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage. Cell Commun Signal 2021; 19:31. [PMID: 33691728 PMCID: PMC7945333 DOI: 10.1186/s12964-021-00712-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/25/2021] [Indexed: 02/06/2023] Open
Abstract
The intestinal epithelium acts as a physical barrier that separates the intestinal microbiota from the host and is critical for preserving intestinal homeostasis. The barrier is formed by tightly linked intestinal epithelial cells (IECs) (i.e. enterocytes, goblet cells, neuroendocrine cells, tuft cells, Paneth cells, and M cells), which constantly self-renew and shed. IECs also communicate with microbiota, coordinate innate and adaptive effector cell functions. In this review, we summarize the signaling pathways contributing to intestinal cell fates and homeostasis functions. We focus especially on intestinal stem cell proliferation, cell junction formation, remodelling, hypoxia, the impact of intestinal microbiota, the immune system, inflammation, and metabolism. Recognizing the critical role of KRAS mutants in colorectal cancer, we highlight the connections of KRAS signaling pathways in coordinating these functions. Furthermore, we review the impact of KRAS colorectal cancer mutants on pathway rewiring associated with disruption and dysfunction of the normal intestinal homeostasis. Given that KRAS is still considered undruggable and the development of treatments that directly target KRAS are unlikely, we discuss the suitability of targeting pathways downstream of KRAS as well as alterations of cell extrinsic/microenvironmental factors as possible targets for modulating signaling pathways in colorectal cancer.
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