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Chen T, Xu Y, Yang F, Pan Y, Ji N, Li J, Zeng X, Chen Q, Jiang L, Shen YQ. Crosstalk of glutamine metabolism between cancer-associated fibroblasts and cancer cells. Cell Signal 2025; 133:111874. [PMID: 40381975 DOI: 10.1016/j.cellsig.2025.111874] [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: 04/14/2025] [Revised: 05/06/2025] [Accepted: 05/14/2025] [Indexed: 05/20/2025]
Abstract
Glutamine (Gln), a critical metabolic substrate, fuels the uncontrolled proliferation of cancer cells. Cancer-associated fibroblasts (CAFs), essential components of the tumor microenvironment, facilitate tumor progression by supplying Gln to cancer cells and driving drug resistance through metabolic reprogramming. This review highlights the key processes of Gln uptake, transport, and catabolism and explores the metabolic crosstalk between CAFs and cancer cells. It also examines the roles of major oncogenic regulators-c-Myc, mTORC, KRAS, p53, and HIF-in controlling Gln metabolism and shaping therapeutic resistance. Current pharmacological approaches targeting Gln metabolism, including enzyme inhibitors and transporter blockers, are discussed alongside emerging therapeutic strategies and ongoing clinical trials. Lastly, we underscore the importance of integrating advanced technologies like artificial intelligence and spatial omics to refine treatment targeting and develop more effective, personalized therapeutic interventions.
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Affiliation(s)
- Tingyu Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yiming Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fan Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yanxin Pan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ning Ji
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jing Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xin Zeng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lu Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ying-Qiang Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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Emami A, Mahdavi Sharif P, Rezaei N. KRAS mutations in colorectal cancer: impacts on tumor microenvironment and therapeutic implications. Expert Opin Ther Targets 2025:1-23. [PMID: 40320681 DOI: 10.1080/14728222.2025.2500426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 04/24/2025] [Indexed: 05/08/2025]
Abstract
INTRODUCTION Despite decreasing trends in incidence, colorectal cancer (CRC) is still a major contributor to malignancy-related morbidities and mortalities. Groundbreaking advances in immunotherapies and targeted therapies benefit a subset of CRC patients, with sub-optimal outcomes. Hence, there is an unmet need to design and manufacture novel therapies, especially for advanced/metastatic disease. KRAS, the most highly mutated proto-oncogene across human malignancies, particularly in pancreatic adenocarcinoma, non-small cell lung cancer, and CRC, is an on-off switch and governs several fundamental cell signaling cascades. KRAS mutations not only propel the progression and metastasis of CRC but also critically modulate responses to targeted therapies. AREAS COVERED We discuss the impacts of KRAS mutations on the CRC's tumor microenvironment and describe novel strategies for targeting KRAS and its associated signaling cascades and mechanisms of drug resistance. EXPERT OPINION Drug development against KRAS mutations has been challenging, mainly due to structural properties (offering no appropriate binding site for small molecules), critical functions of the wild-type KRAS in non-cancerous cells, and the complex network of its downstream effector pathways (allowing malignant cells to develop resistance). Pre-clinical and early clinical data offer promises for combining KRAS inhibitors with immunotherapies and targeted therapies.
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Affiliation(s)
- Anita Emami
- Tehran University of Medical Sciences, Tehran, Iran
| | | | - Nima Rezaei
- Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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3
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Takeda M, Yoshida S, Inoue T, Sekido Y, Hata T, Hamabe A, Ogino T, Miyoshi N, Uemura M, Yamamoto H, Doki Y, Eguchi H. The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives. Cancers (Basel) 2025; 17:428. [PMID: 39941797 PMCID: PMC11816235 DOI: 10.3390/cancers17030428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 01/17/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, with KRAS mutations occurring in 30-40% of cases, contributing to poor prognosis and resistance to anti-EGFR therapy. This review explores the biological significance, clinical implications, and therapeutic targeting of KRAS mutations in CRC. Methods: A comprehensive analysis of the existing literature and clinical trials was performed, highlighting the role of KRAS mutations in CRC pathogenesis, their impact on prognosis, and recent advancements in targeted therapies. Specific attention was given to emerging therapeutic strategies and resistance mechanisms. Results: KRAS mutations drive tumor progression through persistent activation of MAPK/ERK and PI3K/AKT signaling pathways. These mutations influence the tumor microenvironment, cancer stem cell formation, macropinocytosis, and cell competition. KRAS-mutant CRC exhibits poor responsiveness to anti-EGFR monoclonal antibodies and demonstrates primary and acquired resistance to KRAS inhibitors. Recent breakthroughs include the development of KRAS G12C inhibitors (sotorasib and adagrasib) and promising agents targeting G12D mutations. However, response rates in CRC remain suboptimal compared to other cancers, necessitating combination therapies and novel approaches, such as vaccines, nucleic acid-based therapeutics, and macropinocytosis inhibitors. Conclusions: KRAS mutations are central to CRC pathogenesis and present a significant therapeutic challenge. Advances in KRAS-targeted therapies offer hope for improved outcomes, but resistance mechanisms and organ-specific differences limit efficacy. Continued efforts in personalized treatment strategies and translational research are critical for overcoming these challenges and improving patient survival.
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Affiliation(s)
- Mitsunobu Takeda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
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Hanada K, Kawada K, Obama K. Targeting Asparagine Metabolism in Solid Tumors. Nutrients 2025; 17:179. [PMID: 39796613 PMCID: PMC11722615 DOI: 10.3390/nu17010179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 12/31/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025] Open
Abstract
Reprogramming of energy metabolism to support cellular growth is a "hallmark" of cancer, allowing cancer cells to balance the catabolic demands with the anabolic needs of producing the nucleotides, amino acids, and lipids necessary for tumor growth. Metabolic alterations, or "addiction", are promising therapeutic targets and the focus of many drug discovery programs. Asparagine metabolism has gained much attention in recent years as a novel target for cancer therapy. Asparagine is widely used in the production of other nutrients and plays an important role in cancer development. Nutritional inhibition therapy targeting asparagine has been used as an anticancer strategy and has shown success in the treatment of leukemia. However, in solid tumors, asparagine restriction alone does not provide ideal therapeutic efficacy. Tumor cells initiate reprogramming processes in response to asparagine deprivation. This review provides a comprehensive overview of asparagine metabolism in cancers. We highlight the physiological role of asparagine and current advances in improving survival and overcoming therapeutic resistance.
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Affiliation(s)
- Keita Hanada
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; (K.H.); (K.O.)
- Department of Surgery, Rakuwakai Otowa Hospital, Kyoto 607-8062, Japan
| | - Kenji Kawada
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; (K.H.); (K.O.)
- Department of General Surgery, Kurashiki Central Hospital, Kurashiki 710-8602, Japan
| | - Kazutaka Obama
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan; (K.H.); (K.O.)
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5
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Wang X, Gong W, Xiong X, Jia X, Xu J. Asparagine: A key metabolic junction in targeted tumor therapy. Pharmacol Res 2024; 206:107292. [PMID: 39002867 DOI: 10.1016/j.phrs.2024.107292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/18/2024] [Accepted: 07/03/2024] [Indexed: 07/15/2024]
Abstract
Nutrient bioavailability in the tumor microenvironment plays a pivotal role in tumor proliferation and metastasis. Among these nutrients, glutamine is a key substance that promotes tumor growth and proliferation, and its downstream metabolite asparagine is also crucial in tumors. Studies have shown that when glutamine is exhausted, tumor cells can rely on asparagine to sustain their growth. Given the reliance of tumor cell proliferation on asparagine, restricting its bioavailability has emerged as promising strategy in cancer treatment. For instance, the use of asparaginase, an enzyme that depletes asparagine, has been one of the key chemotherapies for acute lymphoblastic leukemia (ALL). However, tumor cells can adapt to asparagine restriction, leading to reduced chemotherapy efficacy, and the mechanisms by which different genetically altered tumors are sensitized or adapted to asparagine restriction vary. We review the sources of asparagine and explore how limiting its bioavailability impacts the progression of specific genetically altered tumors. It is hoped that by targeting the signaling pathways involved in tumor adaptation to asparagine restriction and certain factors within these pathways, the issue of drug resistance can be addressed. Importantly, these strategies offer precise therapeutic approaches for genetically altered cancers.
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Affiliation(s)
- Xuan Wang
- Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing 210004, China
| | - Weijian Gong
- Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing 210004, China
| | - Xueyou Xiong
- Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing 210004, China
| | - Xuemei Jia
- Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing 210004, China; Nanjing Medical Key Laboratory of Female Fertility Preservation and Restoration, Nanjing 210004, China.
| | - Juan Xu
- Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing 210004, China; Nanjing Medical Key Laboratory of Female Fertility Preservation and Restoration, Nanjing 210004, China.
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6
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Yuan Q, Yin L, He J, Zeng Q, Liang Y, Shen Y, Zu X. Metabolism of asparagine in the physiological state and cancer. Cell Commun Signal 2024; 22:163. [PMID: 38448969 PMCID: PMC10916255 DOI: 10.1186/s12964-024-01540-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 02/22/2024] [Indexed: 03/08/2024] Open
Abstract
Asparagine, an important amino acid in mammals, is produced in several organs and is widely used for the production of other nutrients such as glucose, proteins, lipids, and nucleotides. Asparagine has also been reported to play a vital role in the development of cancer cells. Although several types of cancer cells can synthesise asparagine alone, their synthesis levels are insufficient to meet their requirements. These cells must rely on the supply of exogenous asparagine, which is why asparagine is considered a semi-essential amino acid. Therefore, nutritional inhibition by targeting asparagine is often considered as an anti-cancer strategy and has shown success in the treatment of leukaemia. However, asparagine limitation alone does not achieve an ideal therapeutic effect because of stress responses that upregulate asparagine synthase (ASNS) to meet the requirements for asparagine in cancer cells. Various cancer cells initiate different reprogramming processes in response to the deficiency of asparagine. Therefore, it is necessary to comprehensively understand the asparagine metabolism in cancers. This review primarily discusses the physiological role of asparagine and the current progress in the field of cancer research.
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Affiliation(s)
- Qiong Yuan
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Liyang Yin
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
| | - Jun He
- Department of Spine Surgery, The Nanhua Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Qiting Zeng
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Yuxin Liang
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Yingying Shen
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.
| | - Xuyu Zu
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.
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7
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Li X, Peng X, Li Y, Wei S, He G, Liu J, Li X, Yang S, Li D, Lin W, Fang J, Yang L, Li H. Glutamine addiction in tumor cell: oncogene regulation and clinical treatment. Cell Commun Signal 2024; 22:12. [PMID: 38172980 PMCID: PMC10763057 DOI: 10.1186/s12964-023-01449-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/19/2023] [Indexed: 01/05/2024] Open
Abstract
After undergoing metabolic reprogramming, tumor cells consume additional glutamine to produce amino acids, nucleotides, fatty acids, and other substances to facilitate their unlimited proliferation. As such, the metabolism of glutamine is intricately linked to the survival and progression of cancer cells. Consequently, targeting the glutamine metabolism presents a promising strategy to inhibit growth of tumor cell and cancer development. This review describes glutamine uptake, metabolism, and transport in tumor cells and its pivotal role in biosynthesis of amino acids, fatty acids, nucleotides, and more. Furthermore, we have also summarized the impact of oncogenes like C-MYC, KRAS, HIF, and p53 on the regulation of glutamine metabolism and the mechanisms through which glutamine triggers mTORC1 activation. In addition, role of different anti-cancer agents in targeting glutamine metabolism has been described and their prospective applications are assessed.
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Affiliation(s)
- Xian Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Xueqiang Peng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Yan Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Shibo Wei
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Guangpeng He
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Jiaxing Liu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Xinyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Shuo Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Dai Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Weikai Lin
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Jianjun Fang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Liang Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
| | - Hangyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
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Blachier J, Cleret A, Guerin N, Gil C, Fanjat JM, Tavernier F, Vidault L, Gallix F, Rama N, Rossignol R, Piedrahita D, Andrivon A, Châlons-Cottavoz M, Aguera K, Gay F, Horand F, Laperrousaz B. L-asparaginase anti-tumor activity in pancreatic cancer is dependent on its glutaminase activity and resistance is mediated by glutamine synthetase. Exp Cell Res 2023; 426:113568. [PMID: 36967104 DOI: 10.1016/j.yexcr.2023.113568] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/13/2023] [Accepted: 03/21/2023] [Indexed: 03/31/2023]
Abstract
l-Asparaginase is a cornerstone of acute lymphoblastic leukemia (ALL) therapy since lymphoblasts lack asparagine synthetase (ASNS) and rely on extracellular asparagine availability for survival. Resistance mechanisms are associated with increased ASNS expression in ALL. However, the association between ASNS and l-Asparaginase efficacy in solid tumors remains unclear, thus limiting clinical development. Interestingly, l-Asparaginase also has a glutaminase co-activity that is crucial in pancreatic cancer where KRAS mutations activate glutamine metabolism. By developing l-Asparaginase-resistant pancreatic cancer cells and using OMICS approaches, we identified glutamine synthetase (GS) as a marker of resistance to l-Asparaginase. GS is the only enzyme able to synthesize glutamine, and its expression also correlates with l-Asparaginase efficacy in 27 human cell lines from 11 cancer indications. Finally, we further demonstrated that GS inhibition prevents cancer cell adaptation to l-Asparaginase-induced glutamine starvation. These findings could pave the way to the development of promising drug combinations to overcome l-Asparaginase resistance.
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Wu Z, Fang ZX, Hou YY, Wu BX, Deng Y, Wu HT, Liu J. Review of ferroptosis in colorectal cancer: Friends or foes? World J Gastroenterol 2023; 29:469-486. [PMID: 36688016 PMCID: PMC9850932 DOI: 10.3748/wjg.v29.i3.469] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/30/2022] [Accepted: 12/21/2022] [Indexed: 01/12/2023] Open
Abstract
Ferroptosis is a newly discovered type of cell-regulated death. It is characterized by the accumulation of iron-dependent lipid peroxidation and can be distinguished from other forms of cell-regulated death by different morphology, biochemistry, and genetics. Recently, studies have shown that ferroptosis is associated with a variety of diseases, including liver, kidney and neurological diseases, as well as cancer. Ferroptosis has been shown to be associated with colorectal epithelial disorders, which can lead to cancerous changes in the gut. However, the potential role of ferroptosis in the occurrence and development of colorectal cancer (CRC) is still controversial. To elucidate the underlying mechanisms of ferroptosis in CRC, this article systematically reviews ferroptosis, and its cellular functions in CRC, for furthering the understanding of the pathogenesis of CRC to aid clinical treatment.
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Affiliation(s)
- Zheng Wu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bing-Xuan Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu Deng
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Okamoto M, Mizuno R, Kawada K, Itatani Y, Kiyasu Y, Hanada K, Hirata W, Nishikawa Y, Masui H, Sugimoto N, Tamura T, Inamoto S, Sakai Y, Obama K. Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase. Int J Mol Sci 2023; 24:ijms24021118. [PMID: 36674635 PMCID: PMC9867023 DOI: 10.3390/ijms24021118] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 12/30/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Neutrophil extracellular traps (NETs) play important roles in host immunity, as there is increasing evidence of their contribution to the progression of several types of cancers even though their role in colorectal cancers (CRCs) remains unclear. To investigate the clinical relevance of NETs in CRCs, we examined the expression of citrullinated histone H3 using immunohistochemistry and preoperative serum myeloperoxidase-DNA complexes in CRC patients using an enzyme-linked immunosorbent assay. High expression of intratumoral or systemic NETs was found to correlate with poor relapse-free survival (RFS), for which it is an independent prognostic factor. In vitro investigations of CRC cells (HCT116, HT29) revealed that NETs did not affect their proliferation but did promote the migration of CRC cells mediated by neutrophil elastase (NE) released during NETosis to increase extracellular signal-regulated kinase (ERK) activity. In vivo experiments using nude mice (KSN/slc) revealed that NE inhibition suppressed liver metastases in CRC cells, although it did not affect the growth of subcutaneously implanted tumors. Taken together, these results suggest that NET formation correlates with poor prognoses of patients with CRC and that the inhibition of NE could be a potential therapy for CRC metastases.
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Affiliation(s)
- Michio Okamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Rei Mizuno
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Department of Surgery, Uji-Tokushukai Medical Center, Kyoto 611-0041, Japan
- Correspondence: ; Tel.: +81-75-751-3445
| | - Kenji Kawada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Department of Surgery, Kurashiki Central Hospital, Okayama 710-8602, Japan
| | - Yoshiro Itatani
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Yoshiyuki Kiyasu
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Keita Hanada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Wataru Hirata
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Yasuyo Nishikawa
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Hideyuki Masui
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Naoko Sugimoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Takuya Tamura
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Susumu Inamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Department of Surgery, Japanese Red Cross Osaka Hospital, Osaka 543-8555, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Department of Surgery, Japanese Red Cross Osaka Hospital, Osaka 543-8555, Japan
| | - Kazutaka Obama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
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Nishikawa G, Kawada K, Hanada K, Maekawa H, Itatani Y, Miyoshi H, Taketo MM, Obama K. Targeting Asparagine Synthetase in Tumorgenicity Using Patient-Derived Tumor-Initiating Cells. Cells 2022; 11:cells11203273. [PMID: 36291140 PMCID: PMC9600002 DOI: 10.3390/cells11203273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/16/2022] Open
Abstract
Reprogramming of energy metabolism is regarded as one of the hallmarks of cancer; in particular, oncogenic RAS has been shown to be a critical regulator of cancer metabolism. Recently, asparagine metabolism has been heavily investigated as a novel target for cancer treatment. For example, Knott et al. showed that asparagine bioavailability governs metastasis in a breast cancer model. Gwinn et al. reported the therapeutic vulnerability of asparagine biosynthesis in KRAS-driven non-small cell lung cancer. We previously reported that KRAS-mutated CRC cells can adapt to glutamine depletion through upregulation of asparagine synthetase (ASNS), an enzyme that synthesizes asparagine from aspartate. In our previous study, we assessed the efficacy of asparagine depletion using human cancer cell lines. In the present study, we evaluated the clinical relevance of asparagine depletion using a novel patient-derived spheroid xenograft (PDSX) mouse model. First, we examined ASNS expression in 38 spheroid lines and found that 12 lines (12/37, 32.4%) displayed high ASNS expression, whereas 26 lines (25/37, 67.6%) showed no ASNS expression. Next, to determine the role of asparagine metabolism in tumor growth, we established ASNS-knockdown spheroid lines using lentiviral short hairpin RNA constructs targeting ASNS. An in vitro cell proliferation assay demonstrated a significant decrease in cell proliferation upon asparagine depletion in the ASNS-knockdown spheroid lines, and this was not observed in the control spheroids lines. In addition, we examined asparagine inhibition with the anti-leukemia drug L-asparaginase (L-Asp) and observed a considerable reduction in cell proliferation at a low concentration (0.1 U/mL) in the ASNS-knockdown spheroid lines, whereas it exhibited limited inhibition of control spheroid lines at the same concentration. Finally, we used the PDSX model to assess the effects of asparagine depletion on tumor growth in vivo. The nude mice injected with ASNS-knockdown or control spheroid lines were administered with L-Asp once a day for 28 days. Surprisingly, in mice injected with ASNS-knockdown spheroids, the administration of L-Asp dramatically inhibited tumor engraftment. On the other hands, in mice injected with control spheroids, the administration of L-Asp had no effect on tumor growth inhibition at all. These results suggest that ASNS inhibition could be critical in targeting asparagine metabolism in cancers.
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Affiliation(s)
- Gen Nishikawa
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
- Department of Surgery, Kyoto City Hospital, Kyoto 604-8845, Japan
| | - Kenji Kawada
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
- Correspondence: ; Tel.: +81-75-366-7595
| | - Keita Hanada
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
- Department of Surgery, Rakuwakai Otowa Hospital, Kyoto 607-8062, Japan
| | - Hisatsugu Maekawa
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Yoshiro Itatani
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Hiroyuki Miyoshi
- Institute for Advancement of Clinical and Translational Science (IACT), Kyoto University Hospital, Kyoto 606-8507, Japan
| | - Makoto Mark Taketo
- Institute for Advancement of Clinical and Translational Science (IACT), Kyoto University Hospital, Kyoto 606-8507, Japan
| | - Kazutaka Obama
- Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
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Chen H, Xu S, Hu Z, Wei Y, Zhu Y, Fang S, Pan Q, Liu K, Li N, Zhu L, Xu G. Bioinformatics algorithm for lung adenocarcinoma based on macropinocytosis-related long noncoding RNAs as a reliable indicator for predicting survival outcomes and selecting suitable anti-tumor drugs. Medicine (Baltimore) 2022; 101:e30543. [PMID: 36197217 PMCID: PMC9509037 DOI: 10.1097/md.0000000000030543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
As a highly conserved endocytic mechanism during evolution, macropinocytosis is enhanced in several malignant tumors, which promotes tumor growth by ingesting extracellular nutrients. Recent research has emphasized the crucial role of macropinocytosis in tumor immunity. In the present study, we established a new macropinocytosis-related algorithm comprising molecular subtypes and a prognostic signature, in which patients with lung adenocarcinoma (LUAD) were classified into different clusters and risk groups based on the expression of 16 macropinocytosis-related long noncoding RNAs. According to the molecular subtypes, we discovered that patients with LUAD in cluster1 had a higher content of stromal cells and immune cells, stronger intensity of immune activities, higher expression of PD1, PDL1, and HAVCR2, and a higher tumor mutational burden, while patients in cluster2 exhibited better survival advantages. Furthermore, the constructed prognostic signature revealed that low-risk patients showed better survival outcomes, earlier tumor stage, higher abundance of stromal cells and immune cells, higher immune activities, higher expression of PD1, PDL1, CTLA4, and HAVCR2, and more sensitivity to Paclitaxel and Erlotinib. By contrast, patients with high scores were more suitable for Gefitinib treatment. In conclusion, the novel algorithm that divided patients with LUAD into different groups according to their clusters and risk groups, which could provide theoretical support for predicting their survival outcomes and selecting drugs for chemotherapy, targeted therapy, and immunotherapy.
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Affiliation(s)
- Hang Chen
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Shuguang Xu
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Zeyang Hu
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Yiqing Wei
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Youjie Zhu
- Department of Respiratory Medicine, Ningbo Huamei Hospital, Chinese Academy of Sciences, Ningbo, Zhejiang, China
| | - Shenzhe Fang
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Qiaoling Pan
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Kaitai Liu
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Ni Li
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Linwen Zhu
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Guodong Xu
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- *Correspondence: Guodong Xu, Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China (e-mail: )
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Shen X, Jain A, Aladelokun O, Yan H, Gilbride A, Ferrucci LM, Lu L, Khan SA, Johnson CH. Asparagine, colorectal cancer, and the role of sex, genes, microbes, and diet: A narrative review. Front Mol Biosci 2022; 9:958666. [PMID: 36090030 PMCID: PMC9453556 DOI: 10.3389/fmolb.2022.958666] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/21/2022] [Indexed: 02/05/2023] Open
Abstract
Asparagine (Asn) and enzymes that catalyze the metabolism of Asn have been linked to the regulation and propagation of colorectal cancer (CRC). Increased Asn and asparagine synthetase (ASNS) expression, both contribute to CRC progression and metastasis. In contradistinction, L-asparaginase (ASNase) which breaks down Asn, exhibits an anti-tumor effect. Metabolic pathways such as KRAS/PI3K/AKT/mTORC1 signaling and high SOX12 expression can positively regulate endogenous Asn production. Conversely, the tumor suppressor, TP53, negatively impacts ASNS, thus limiting Asn synthesis and reducing tumor burden. Asn abundance can be altered by factors extrinsic to the cancer cell such as diet, the microbiome, and therapeutic use of ASNase. Recent studies have shown that sex-related factors can also influence the regulation of Asn, and high Asn production results in poorer prognosis for female CRC patients but not males. In this narrative review, we critically review studies that have examined endogenous and exogenous modulators of Asn bioavailability and summarize the key metabolic networks that regulate Asn metabolism. We also provide new hypotheses regarding sex-related influences on Asn, including the involvement of the sex-steroid hormone estrogen and estrogen receptors. Further, we hypothesize that sex-specific factors that influence Asn metabolism can influence clinical outcomes in CRC patients.
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Affiliation(s)
- Xinyi Shen
- Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, United States
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Abhishek Jain
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Oladimeji Aladelokun
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Hong Yan
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Austin Gilbride
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Leah M. Ferrucci
- Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Lingeng Lu
- Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, United States
| | - Sajid A. Khan
- Division of Surgical Oncology, Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
| | - Caroline H. Johnson
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States
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14
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Qiu Z, Liu W, Zhu Q, Ke K, Zhu Q, Jin W, Yu S, Yang Z, Li L, Sun X, Ren S, Liu Y, Zhu Z, Zeng J, Huang X, Huang Y, Wei L, Ma M, Lu J, Chen X, Mou Y, Xie T, Sui X. The Role and Therapeutic Potential of Macropinocytosis in Cancer. Front Pharmacol 2022; 13:919819. [PMID: 36046825 PMCID: PMC9421435 DOI: 10.3389/fphar.2022.919819] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 06/17/2022] [Indexed: 11/20/2022] Open
Abstract
Macropinocytosis, a unique endocytosis pathway characterized by nonspecific internalization, has a vital role in the uptake of extracellular substances and antigen presentation. It is known to have dual effects on cancer cells, depending on cancer type and certain microenvironmental conditions. It helps cancer cells survive in nutrient-deficient environments, enhances resistance to anticancer drugs, and promotes invasion and metastasis. Conversely, overexpression of the RAS gene alongside drug treatment can lead to methuosis, a novel mode of cell death. The survival and proliferation of cancer cells is closely related to macropinocytosis in the tumor microenvironment (TME), but identifying how these cells interface with the TME is crucial for creating drugs that can limit cancer progression and metastasis. Substantial progress has been made in recent years on designing anticancer therapies that utilize the effects of macropinocytosis. Both the induction and inhibition of macropinocytosis are useful strategies for combating cancer cells. This article systematically reviews the general mechanisms of macropinocytosis, its specific functions in tumor cells, its occurrence in nontumor cells in the TME, and its application in tumor therapies. The aim is to elucidate the role and therapeutic potential of macropinocytosis in cancer treatment.
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Affiliation(s)
- Zejing Qiu
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Wencheng Liu
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Qianru Zhu
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Kun Ke
- Department of Gastrointestinal-Pancreatic Surgery, General Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Qicong Zhu
- Department of Gastrointestinal-Pancreatic Surgery, General Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Weiwei Jin
- Department of Gastrointestinal-Pancreatic Surgery, General Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Shuxian Yu
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Zuyi Yang
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Lin Li
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Xiaochen Sun
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Shuyi Ren
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Yanfen Liu
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Zhiyu Zhu
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Jiangping Zeng
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Xiaoyu Huang
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Yan Huang
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Lu Wei
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Mengmeng Ma
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Jun Lu
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Xiaoyang Chen
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Yiping Mou
- Department of Gastrointestinal-Pancreatic Surgery, General Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
- *Correspondence: Yiping Mou, ; Tian Xie, ; Xinbing Sui,
| | - Tian Xie
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
- *Correspondence: Yiping Mou, ; Tian Xie, ; Xinbing Sui,
| | - Xinbing Sui
- Department of Medical Oncology and School of Pharmacy, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
- *Correspondence: Yiping Mou, ; Tian Xie, ; Xinbing Sui,
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15
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Peng X, Zheng T, Guo Y, Zhu Y. Amino acid metabolism genes associated with immunotherapy responses and clinical prognosis of colorectal cancer. Front Mol Biosci 2022; 9:955705. [PMID: 35992263 PMCID: PMC9388734 DOI: 10.3389/fmolb.2022.955705] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 07/05/2022] [Indexed: 11/13/2022] Open
Abstract
Based on amino acid metabolism-related genes (AAMRGs), this study aimed at screening out key prognosis-related genes and finding the underlying correlation between the amino acid metabolism and tumor immune microenvironment of colorectal cancer. A total of 448 amino acid metabolism-related genes were obtained from MsigDB. The risk signature was built based on differential expression genes, univariate Cox, and LASSO analyses with 403 patients’ data downloaded from the TCGA database. Survival analysis and independence tests were performed to confirm the validity of the risk signature. Single-sample gene set enrichment analysis (ssGSEA), tumor mutation burden (TMB), the score of tumor immune dysfunction and exclusion (TIDE), the immunophenoscore obtained from The Cancer Immunome Atlas database, and the IC50 of drugs were used to find the relationship among the risk signature, immune status, immunotherapy response, and drug sensitivity of colorectal cancer. We identified five amino acid metabolism-related genes for the construction of the risk signature, including ENOPH1, ACAT1, ALDH4A1, FAS, and ASPG. The low-risk group was significantly associated with a better prognosis (p < 0.0001). In the entire set, the area under the curve (AUC) for 1, 3, and 5 years was 0.717, 0.734, and 0.764, respectively. We also discovered that the low-risk subgroup was related to more activity of immune cells, had higher expression of some immune checkpoints, and was more likely to benefit from immunotherapy. ssGSEA revealed that except the processes of glutamine histidine, lysine, tyrosine, and L-phenylalanine metabolism, the other amino acid metabolism pathways were more active in the samples with the low risk scores, whereas the activities of synthesis and transportation of most amino acids were similar. Hedgehog signaling, WNT/β-catenin signaling, mitotic, notch signaling, and TGF-β signaling were the top five pathways positively associated with the risk score. To sum up, AAMRGs were associated with the immune microenvironment of CRC patients and could be applied as biomarkers to predict the prognosis and immunotherapy response of patients.
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Affiliation(s)
- Xinyi Peng
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Department of Oncology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Ting Zheng
- Hangzhou Hikvision Digital Technology Co, Ltd, Zhejiang, China
| | - Yong Guo
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Department of Oncology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
- *Correspondence: Ying Zhu, ; Yong Guo,
| | - Ying Zhu
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Department of Oncology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
- *Correspondence: Ying Zhu, ; Yong Guo,
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16
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Gregorio JD, Petricca S, Iorio R, Toniato E, Flati V. MITOCHONDRIAL AND METABOLIC ALTERATIONS IN CANCER CELLS. Eur J Cell Biol 2022; 101:151225. [DOI: 10.1016/j.ejcb.2022.151225] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 04/11/2022] [Accepted: 04/11/2022] [Indexed: 02/07/2023] Open
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