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1
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Jiang M, Ma S, Xuan Y, Chen K. Synthetic approaches and clinical application of KRAS inhibitors for cancer therapy. Eur J Med Chem 2025; 291:117626. [PMID: 40252381 DOI: 10.1016/j.ejmech.2025.117626] [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: 03/18/2025] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 04/21/2025]
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic alterations in various cancers, including pancreatic, colorectal, and non-small cell lung cancer (NSCLC). Targeting KRAS has long been considered a difficult challenge due to its high affinity for guanosine triphosphate (GTP) and the lack of a druggable binding site. However, recent advancements in small-molecule inhibitor design have led to the development of targeted therapies aimed at KRAS mutations, particularly the KRASG12C mutation. Inhibitors such as Sotorasib and Adagrasib have shown promise in preclinical and clinical studies by irreversibly binding to the mutant KRAS protein, locking it in an inactive state and disrupting downstream signaling pathways critical for tumor growth and survival. These inhibitors have demonstrated clinical efficacy in treating patients with KRASG12C-mutated cancers, leading to tumor regression, prolonged progression-free survival, and improved patient outcomes. This review discusses the synthetic strategies employed to develop these KRAS inhibitor and also examines the clinical application of these inhibitors, highlighting the challenges and successes encountered during clinical trials. Ultimately, KRAS inhibitors represent a breakthrough in cancer therapy, offering a promising new treatment option for patients with KRAS-driven tumors.
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Affiliation(s)
- Min Jiang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Shaowei Ma
- Department of Interventional Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ying Xuan
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
| | - Kuanbing Chen
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China.
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2
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Liu B, Yang T, Zhang J, Li H. UFMylation in tumorigenesis: Mechanistic insights and therapeutic opportunities. Cell Signal 2025; 129:111657. [PMID: 39954715 DOI: 10.1016/j.cellsig.2025.111657] [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: 12/11/2024] [Revised: 02/09/2025] [Accepted: 02/12/2025] [Indexed: 02/17/2025]
Abstract
Post-translational modification (PTM) is an essential mechanism that regulates protein function within cells, influencing aspects such as protein activity, stability, subcellular localization, and interactions with other molecules through the addition or removal of chemical groups on amino acid residues. One notable type of PTM is UFMylation, a recently discovered modification process that involves the covalent attachment of UFM1 to lysine residues on target proteins. This process is facilitated by a specific enzyme system that includes the UFM1-activating enzyme, the UFM1-conjugating enzyme, and the UFM1-specific ligase. UFMylation is crucial for various cellular functions, such as responding to endoplasmic reticulum stress and DNA-damage response, and it is linked to the development and progression of several human diseases, including cancers, highlighting its importance in biological processes. Despite this significance, the range of substrates, regulatory mechanisms, and biological processes associated with UFMylation are not well understood, with only a few substrates having been characterized. Here, we focus on the molecular mechanisms of UFMylation, its implications in tumorigenesis, and its interactions with tumor suppressive and oncogenic signaling pathways. Furthermore, we employed bioinformatics approaches to analyze UFMylation's role in cancer, focusing on expression profiles, mutations, prognosis, drug sensitivity, and immune infiltration to explore its therapeutic potential in immunotherapy.
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Affiliation(s)
- Bingtao Liu
- Radiotherapy center, Gansu Provincial Maternity and Child-care Hospital (Gansu Provincial Central Hospital), Lanzhou 730050, China
| | - Tiantian Yang
- School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050, China
| | - Jialin Zhang
- School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050, China
| | - Hongbin Li
- School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050, China.
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3
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Yuan T, Liu Y, Wu R, Qian M, Wang W, Li Y, Zhu H, Wang J, Ge F, Zeng C, Dai X, Hu R, Zhou T, He Q, Zhu H, Yang B. Josephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancer. Nat Commun 2025; 16:3623. [PMID: 40240366 PMCID: PMC12003847 DOI: 10.1038/s41467-025-58923-y] [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: 07/30/2024] [Accepted: 04/07/2025] [Indexed: 04/18/2025] Open
Abstract
KRAS is the most common mutated oncogenes in colorectal cancer (CRC), yet effective therapeutic strategies for targeting multiple KRAS mutations remained challenging. The prolonged protein stability of KRAS mutants contribute to their robust tumor-promoting effects, but the underlying mechanism is elusive. Herein by screening deubiquitinases (DUBs) siRNA library, we identify Josephin domain containing 2 (JOSD2) functions as a potent DUB that regulates the protein stability of KRAS mutants. Mechanistically, JOSD2 directly interacts with and stabilizes KRAS variants across different mutants, by reverting their proteolytic ubiquitination; while KRAS mutants reciprocally inhibit the catalytic activity of CHIP, a bona fide E3 ubiquitin ligase for JOSD2, thus forming a JOSD2/KRAS positive feedback circuit that significantly accelerates KRAS-mutant CRC growth. Inhibition of JOSD2 by RNA interference or its pharmacological inhibitor promotes the polyubiquitination and proteasomal degradation of KRAS mutants, and preferentially impede the growth of KRAS-mutant CRC including patient-derived cells/xenografts/organoids (PDCs/PDXs/PDOs) over that harboring wild-type KRAS. Collectively, this study not only reveals the crucial roles of JOSD2/KRAS positive feedback circuit in KRAS-mutant CRC, but also provides a rationale to target JOSD2 as the promising pan-KRAS-mutation-targeting strategy for the treatment of a broad population of CRC patients with KRAS variant across different mutant types.
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Affiliation(s)
- Tao Yuan
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yue Liu
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Ruilin Wu
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Meijia Qian
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Weihua Wang
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yonghao Li
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hongdao Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jia'er Wang
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Fujing Ge
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Chenming Zeng
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoyang Dai
- Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, China
| | - Ronggui Hu
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tianhua Zhou
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiaojun He
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, China
| | - Hong Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Bo Yang
- Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
- School of Medicine, Hangzhou City University, Hangzhou, China.
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Hu Y, Zheng J, Chen YJ, Pu WY, Xu YJ, Dong L. Stereoselective synthesis of a KRAS G12C inhibitor with a quinoline-piperazine scaffold. Org Biomol Chem 2025; 23:3194-3198. [PMID: 40052217 DOI: 10.1039/d4ob02104e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
We developed a novel synthetic route for the KRASG12C inhibitor, focusing on the efficient construction of its central quinoline scaffold. The method offers several advantages: eliminates the formation of regioselective by-products and avoids the use of high temperatures and nitric acid. The last step of the overall route enables gentle hydrolysis of phenyl esters with methanol and potassium carbonate, which greatly reduces the occurrence of side reactions. In addition, the stereoisomers were successfully separated by silica gel column chromatography.
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Affiliation(s)
- Ying Hu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
- College of Chemistry and Material Science, Sichuan Normal University, Chengdu, Sichuan 610066, China.
| | - Jing Zheng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
| | - Yin-Jun Chen
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
| | - Wei-Yi Pu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
| | - Yan-Jun Xu
- College of Chemistry and Material Science, Sichuan Normal University, Chengdu, Sichuan 610066, China.
| | - Lin Dong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
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5
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Yang C, Li HX, Gan H, Shuai X, Dong C, Wang W, Lin D, Zhong B. KRAS4B oncogenic mutants promote non-small cell lung cancer progression via the interaction of deubiquitinase USP25 with RNF31. Dev Cell 2025:S1534-5807(25)00035-8. [PMID: 39952242 DOI: 10.1016/j.devcel.2025.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 09/30/2024] [Accepted: 01/24/2025] [Indexed: 02/17/2025]
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogenic mutations are genetic drivers in various cancers, including non-small cell lung cancer (NSCLC). However, the regulatory mechanisms underlying the progression of NSCLC driven by oncogenic KRAS mutants are incompletely understood. Here, we show that ubiquitin specific peptidase 25 (USP25) impedes ring finger protein 31 (RNF31)-mediated linear ubiquitination of KRAS oncogenic mutants (KRASmuts) independently of its deubiquitinase activity, which facilitates the plasma membrane (PM) localization and the downstream oncogenic signaling of KRASmuts. Importantly, knockout (KO) of USP25 effectively suppresses tumor growth and RAS signaling in KRASmuts-driven autochthonous NSCLC mouse models and xenograft models, which is restored by additional deletion or inhibition of RNF31. Notably, knockin of USP25C178A in KRasG12D-driven NSCLC models fails to inhibit cancer progression and reconstitution of USP25C178A into USP25 KO A549 cells restores tumor growth. These findings identify previously uncharacterized roles of USP25 and RNF31 in oncogenic KRAS-driven NSCLC progression and provide potential therapeutic targets for KRASmuts-related cancers.
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Affiliation(s)
- Ci Yang
- Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Department of Virology, College of Life Sciences, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan University, Wuhan 430072, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China; Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430071, China; Hubei Key Laboratory of Tumor Biological Behavior, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Hong-Xu Li
- Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Department of Virology, College of Life Sciences, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan University, Wuhan 430072, China; Hubei Key Laboratory of Tumor Biological Behavior, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Hu Gan
- Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Department of Virology, College of Life Sciences, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan University, Wuhan 430072, China
| | - Xin Shuai
- Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Department of Virology, College of Life Sciences, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan University, Wuhan 430072, China
| | - Chen Dong
- School of Medicine, Westlake University, Hangzhou 310024, China
| | - Wei Wang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, China.
| | - Dandan Lin
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, China.
| | - Bo Zhong
- Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Department of Virology, College of Life Sciences, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan University, Wuhan 430072, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China; Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430071, China; Hubei Key Laboratory of Tumor Biological Behavior, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
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6
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Koo H, Park KC, Sohn HA, Kang M, Kim DJ, Park ZY, Park S, Min SH, Park SH, You YM, Han Y, Kim BK, Lee CH, Kim YS, Chung SJ, Yeom YI, Lee DC. Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development. Nat Commun 2025; 16:628. [PMID: 39819877 PMCID: PMC11739382 DOI: 10.1038/s41467-024-54476-8] [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: 01/18/2024] [Accepted: 11/12/2024] [Indexed: 01/19/2025] Open
Abstract
Cancers with activating mutations of KRAS show a high prevalence but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression is post-translationally up-regulated through deubiquitination when the scaffolding function of NDRG3 (N-Myc downstream-regulated gene 3) promotes specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant cancer cells KRAS protein expression, downstream signaling, and cell growth are highly dependent on NDRG3. In conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma, Ndrg3 depletion abolishes Kras protein expression and suppresses intraepithelial neoplasia formation in pancreas. Mechanistically, KRAS protein binds to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through deubiquitination by USP9X recruited to the complex. This interaction can be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that binds KRAS but is defective in USP9X binding, highly suppressing KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction.
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Affiliation(s)
- Han Koo
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea
| | - Kyung Chan Park
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea
| | - Hyun Ahm Sohn
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Minho Kang
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Dong Joon Kim
- Department of Microbiology, College of Medicine, Dankook University, Cheonan, Chungcheongnam-do, Korea
- MRCRC, Dankook University, Cheonan, Chungcheongnam-do, Korea
| | - Zee-Yong Park
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Sehoon Park
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Sang Hyun Min
- Department of Innovative Pharmaceutical Sciences, Kyungpook National University, Deagu, Korea
| | - Seong-Hwan Park
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Yeon-Mi You
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea
| | - Yohan Han
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Bo-Kyung Kim
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea
| | - Chul-Ho Lee
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Yeon-Soo Kim
- Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Korea
| | - Sang J Chung
- Department of Biopharmaceutical Convergence, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea
| | - Young Il Yeom
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea.
- College of Pharmacy, Chungnam National University, Daejeon, Korea.
| | - Dong Chul Lee
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea.
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Liu W, Kuai Y, Wang D, Chen J, Xiong F, Wu G, Wang Q, Huang W, Qi Y, Wang B, Chen Y. PPM1G Inhibits Epithelial-Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2407323. [PMID: 39477806 DOI: 10.1002/advs.202407323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/22/2024] [Indexed: 12/19/2024]
Abstract
Ten-eleven translocation protein 1 (TET1) functions as an epigenetic regulatory molecule, mediating the majority of DNA demethylation, and plays a role in the development of different types of cancers by regulating the expression of proto-oncogenes and oncogenes. Here it is found that TET1 is highly expressed in cholangiocarcinoma (CCA) and is associated with a poor prognosis. In addition, TET1 promotes claudin-3 (CLDN3) transcription by targeting the CLDN3 promoter region between -16 and 512 for demethylation. PPM1G functions as a protein dephosphorylase, catalyzing the dephosphorylation of TET1. This results in the destabilization of the TET1 protein, thereby impairing the targeting of the CLDN3 promoter for demethylation. Two phosphatase inhibitors, staurosporine and AZD0156, inhibit epithelial-to-mesenchymal transition (EMT) in cholangiocarcinoma cells by suppressing TET1 expression. In conclusion, it is also demonstrated that PPM1G can be employed as a therapeutic target to impede the progression of CCA by catalyzing the dephosphorylation of TET1, which diminishes the capacity of TET1 to target the CLDN3 promoter to activate transcription and inhibit EMT in CCA.
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Affiliation(s)
- Wenzheng Liu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Yiyang Kuai
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Da Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Junsheng Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Fei Xiong
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Guanhua Wu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Qi Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Wenhua Huang
- Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430074, China
| | - Yongqiang Qi
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Bing Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Yongjun Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
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8
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Li T, Gu C, Zhou C, Mao C, Yang K, Xu J, Lu T, Chen J. Insights into direct KRAS inhibition strategies for cancer treatment. Future Med Chem 2024; 16:2411-2429. [PMID: 39569642 PMCID: PMC11622815 DOI: 10.1080/17568919.2024.2424149] [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: 03/08/2024] [Accepted: 10/23/2024] [Indexed: 11/22/2024] Open
Abstract
KRAS is the most commonly mutated isoform in RAS-driven cancers. In the early stage, KRAS was deemed as an "undruggable" cancer target due to the lack of suitable binding pockets. With the development of KRAS inhibitors in recent years, strategies that directly suppress oncogenic KRAS have achieved significant breakthroughs. In this review, we summarize recent advances in direct small-molecule KRAS inhibitors used for cancer therapy, highlighting their medicinal chemistry optimization processes. Moreover, new PROTACs targeting the KRAS mutation are also presented. Additionally, we put forward the challenges and prospects for the development of future KRAS inhibitors.
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Affiliation(s)
- Tong Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Chenglei Gu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Chen Zhou
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL32610, United States
| | - Chunqin Mao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Kan Yang
- Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, 071002, China
| | - Jinyi Xu
- State Key Laboratory of Natural Medicines & Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Tulin Lu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jichao Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
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9
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Xu X, Peng Q, Jiang X, Tan S, Yang W, Han Y, Oyang L, Lin J, Shen M, Wang J, Li H, Xia L, Peng M, Wu N, Tang Y, Wang H, Liao Q, Zhou Y. Altered glycosylation in cancer: molecular functions and therapeutic potential. Cancer Commun (Lond) 2024; 44:1316-1336. [PMID: 39305520 PMCID: PMC11570773 DOI: 10.1002/cac2.12610] [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: 03/14/2024] [Revised: 08/29/2024] [Accepted: 09/10/2024] [Indexed: 11/19/2024] Open
Abstract
Glycosylation, a key mode of protein modification in living organisms, is critical in regulating various biological functions by influencing protein folding, transportation, and localization. Changes in glycosylation patterns are a significant feature of cancer, are associated with a range of pathological activities in cancer-related processes, and serve as critical biomarkers providing new targets for cancer diagnosis and treatment. Glycoproteins like human epidermal growth factor receptor 2 (HER2) for breast cancer, alpha-fetoprotein (AFP) for liver cancer, carcinoembryonic antigen (CEA) for colon cancer, and prostate-specific antigen (PSA) for prostate cancer are all tumor biomarkers approved for clinical use. Here, we introduce the diversity of glycosylation structures and newly discovered glycosylation substrate-glycosylated RNA (glycoRNA). This article focuses primarily on tumor metastasis, immune evasion, metabolic reprogramming, aberrant ferroptosis responses, and cellular senescence to illustrate the role of glycosylation in cancer. Additionally, we summarize the clinical applications of protein glycosylation in cancer diagnostics, treatment, and multidrug resistance. We envision a promising future for the clinical applications of protein glycosylation.
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Affiliation(s)
- Xuemeng Xu
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Qiu Peng
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Xianjie Jiang
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Shiming Tan
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
| | - Wenjuan Yang
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
| | - Yaqian Han
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Linda Oyang
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Jinguan Lin
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Mengzhou Shen
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Jiewen Wang
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Haofan Li
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
| | - Longzheng Xia
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Mingjing Peng
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Nayiyuan Wu
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Yanyan Tang
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
| | - Hui Wang
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Key Laboratory of Translational Radiation OncologyChangshaHunanP. R. China
| | - Qianjin Liao
- Department of OncologyHunan Provincial People's HospitalThe First Affiliated Hospital of Hunan Normal UniversityChangshaHunanP. R. China
| | - Yujuan Zhou
- The Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University/Hunan Cancer Hospital, Hunan Key Laboratory of Cancer MetabolismChangshaHunanP. R. China
- Hunan Engineering Research Center of Tumor organoid Technology and application, Public Service Platform of Tumor organoids TechnologyChangshaHunanP. R. China
- Hunan Key Laboratory of Translational Radiation OncologyChangshaHunanP. R. China
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10
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Zhu W, Wu C, Liu Z, Zhao S, Huang J. OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2) modulates the stemness feature, chemoresistance, and epithelial-mesenchymal transition of colon cancer via regulating GINS complex subunit 1 (GINS1) expression. Cell Commun Signal 2024; 22:420. [PMID: 39210373 PMCID: PMC11361113 DOI: 10.1186/s12964-024-01789-2] [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: 06/11/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Colon cancer is one of the most prevalent tumors in the digestive tract, and its stemness feature significantly contribute to chemoresistance, promote the epithelial-mesenchymal transition (EMT) process, and ultimately lead to tumor metastasis. Therefore, it is imperative for researchers to elucidate the molecular mechanisms underlying the enhancement of stemness feature, chemoresistance, and EMT in colon cancer. METHODS Sphere-formation and western blotting assays were conducted to assess the stemness feature. Edu, flow cytometry, and cell viability assays were employed to evaluate the chemoresistance. Immunofluorescence and western blotting assays were utilized to detect EMT. Immunoprecipitation, ubiquitination, agarose gel electrophoresis, chromatin immunoprecipitation followed by quantitative PCR (chip-qPCR), and dual luciferase reporter gene assays were employed for mechanistic investigations. RESULTS We demonstrated a markedly higher expression level of OTUB2 in colon cancer tissues compared to adjacent tissues. Furthermore, elevated OTUB2 expression was closely associated with poor prognosis and distant tumor metastasis. Functional experiments revealed that knockdown of OTUB2 attenuated stemness feature of colon cancer, enhanced its sensitivity to oxaliplatin, inhibited its EMT process, ultimately reduced the ability of tumor metastasis. Conversely, overexpression of OTUB2 exerted opposite effects. Mechanistically, we identified OTUB2 as a deubiquitinase for SP1 protein which bound specifically to SP1 protein, thereby inhibiting K48 ubiquitination of SP1 protein. The SP1 protein functioned as a transcription factor for the GINS1, exerting its regulatory effect by binding to the 1822-1830 region of the GINS1 promoter and enhancing its transcriptional activity. Ultimately, alterations in GINS1 expression directly regulated stemness feature, chemosensitivity, and EMT progression in colon cancer. CONCLUSION Collectively, the OTUB2/SP1/GINS1 axis played a pivotal role in driving stemness feature, chemoresistance, and EMT in colon cancer. These results shed new light on understanding chemoresistance and metastasis mechanisms involved in colon cancer.
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Affiliation(s)
- Wenjie Zhu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
- Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Changlei Wu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
- Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Zitao Liu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
- Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - ShiMin Zhao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
- Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Jun Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China.
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11
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Ash LJ, Busia-Bourdain O, Okpattah D, Kamel A, Liberchuk A, Wolfe AL. KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance. Curr Oncol 2024; 31:2024-2046. [PMID: 38668053 PMCID: PMC11049385 DOI: 10.3390/curroncol31040150] [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: 03/13/2024] [Revised: 03/29/2024] [Accepted: 04/01/2024] [Indexed: 04/28/2024] Open
Abstract
KRAS is a small GTPase that is among the most commonly mutated oncogenes in cancer. Here, we discuss KRAS biology, therapeutic avenues to target it, and mechanisms of resistance that tumors employ in response to KRAS inhibition. Several strategies are under investigation for inhibiting oncogenic KRAS, including small molecule compounds targeting specific KRAS mutations, pan-KRAS inhibitors, PROTACs, siRNAs, PNAs, and mutant KRAS-specific immunostimulatory strategies. A central challenge to therapeutic effectiveness is the frequent development of resistance to these treatments. Direct resistance mechanisms can involve KRAS mutations that reduce drug efficacy or copy number alterations that increase the expression of mutant KRAS. Indirect resistance mechanisms arise from mutations that can rescue mutant KRAS-dependent cells either by reactivating the same signaling or via alternative pathways. Further, non-mutational forms of resistance can take the form of epigenetic marks, transcriptional reprogramming, or alterations within the tumor microenvironment. As the possible strategies to inhibit KRAS expand, understanding the nuances of resistance mechanisms is paramount to the development of both enhanced therapeutics and innovative drug combinations.
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Affiliation(s)
- Leonard J. Ash
- Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA
- Molecular, Cellular, and Developmental Biology Subprogram of the Biology Ph.D. Program, Graduate Center, City University of New York, New York, NY 10031, USA
| | - Ottavia Busia-Bourdain
- Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA
| | - Daniel Okpattah
- Biochemistry Ph.D. Program, Graduate Center, City University of New York, New York, NY 10031, USA
| | - Avrosina Kamel
- Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA
- Macaulay Honors College, Hunter College, City University of New York, New York, NY 10065, USA
| | - Ariel Liberchuk
- Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA
- Macaulay Honors College, Hunter College, City University of New York, New York, NY 10065, USA
| | - Andrew L. Wolfe
- Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA
- Molecular, Cellular, and Developmental Biology Subprogram of the Biology Ph.D. Program, Graduate Center, City University of New York, New York, NY 10031, USA
- Biochemistry Ph.D. Program, Graduate Center, City University of New York, New York, NY 10031, USA
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA
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12
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Mouhcine M, Kadil Y, Segmani I, Rahmoune I, Filali H. In silico Exploration of a Novel ICMT Inhibitor with More Solubility than Cysmethynil against Membrane Localization of KRAS Mutant in Colorectal Cancer. Curr Comput Aided Drug Des 2024; 20:1055-1069. [PMID: 38835128 DOI: 10.2174/0115734099264451231003172217] [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: 05/28/2023] [Revised: 08/14/2023] [Accepted: 08/31/2023] [Indexed: 06/06/2024]
Abstract
BACKGROUND ICMT (isoprenylcysteine carboxyl methyltransferase) is an enzyme that plays a key role in the post-translational modification of the K-Ras protein. The carboxyl methylation of this protein by ICMT is important for its proper localization and function. Cysmethynil (2-[5-(3-methylphenyl)-l-octyl-lH-indolo-3-yl] acetamide) causes K-Ras mislocalization and interrupts pathways that control cancer cell growth and division through inhibition of ICMT, but its poor water solubility makes it difficult and impractical for clinical use. This indicates that relatively high amounts of cysmethynil would be required to achieve an effective dose, which could result in significant adverse effects in patients. OBJECTIVE The general objective of this work was to find virtually new compounds that present high solubility in water and are similar to the pharmacological activity of cysmethynil. MATERIALS AND METHODS Pharmacophore modeling, pharmacophore-based virtual screening, prediction of ADMET properties (absorption, distribution, metabolism, excretion, and toxicity), and water solubility were performed to recover a water-soluble molecule that shares the same chemical characteristics as cysmethynil using Discovery Studio v16.1.0 (DS16.1), SwissADME server, and pkCSM server. RESULTS In this study, ten pharmacophore model hypotheses were generated by exploiting the characteristics of cysmethynil. The pharmacophore model validated by the set test method was used to screen the "Elite Library®" and "Synergy Library" databases of Asinex. Only 1533 compounds corresponding to all the characteristics of the pharmacophore were retained. Then, the aqueous solubility in water at 25°C of these 1533 compounds was predicted by the Cheng and Merz model. Among these 1533 compounds, two had the optimal water solubility. Finally, the ADMET properties and Log S water solubility by three models (ESOL, Ali, and SILICOS-IT) of the two compounds and cysmethynil were compared, resulting in compound 2 as a potential inhibitor of ICMT. CONCLUSION According to the results obtained, the identified compound presented a high solubility in water and could be similar to the pharmacological activity of cysmethynil.
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Affiliation(s)
- Mohammed Mouhcine
- Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University of Casablanca, Casablanca, Morocco
| | - Youness Kadil
- Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University of Casablanca, Casablanca, Morocco
| | - Ibtihal Segmani
- Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University of Casablanca, Casablanca, Morocco
| | - Imane Rahmoune
- Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University of Casablanca, Casablanca, Morocco
| | - Houda Filali
- Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University of Casablanca, Casablanca, Morocco
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13
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Li Y, Dobrolecki LE, Sallas C, Zhang X, Kerr TD, Bisht D, Wang Y, Awasthi S, Kaundal B, Wu S, Peng W, Mendillo ML, Lu Y, Jeter CR, Peng G, Liu J, Westin SN, Sood AK, Lewis MT, Das J, Yi SS, Bedford MT, McGrail DJ, Sahni N. PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition. Cell Rep Med 2023; 4:101326. [PMID: 38118413 PMCID: PMC10772459 DOI: 10.1016/j.xcrm.2023.101326] [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: 04/16/2023] [Revised: 09/07/2023] [Accepted: 11/17/2023] [Indexed: 12/22/2023]
Abstract
Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.
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Affiliation(s)
- Yang Li
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lacey E Dobrolecki
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
| | - Christina Sallas
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
| | - Xudong Zhang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Travis D Kerr
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA
| | - Deepa Bisht
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yalong Wang
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sharad Awasthi
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Babita Kaundal
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Siqi Wu
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Weiyi Peng
- Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Marc L Mendillo
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yiling Lu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Collene R Jeter
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Guang Peng
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jinsong Liu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shannon N Westin
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael T Lewis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
| | - Jishnu Das
- Center for Systems Immunology, Department of Immunology, and Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - S Stephen Yi
- Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA; Interdisciplinary Life Sciences Graduate Programs (ILSGP), College of Natural Sciences, The University of Texas at Austin, Austin, TX, USA; Oden Institute for Computational Engineering and Sciences (ICES), The University of Texas at Austin, Austin, TX, USA; Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX, USA
| | - Mark T Bedford
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Daniel J McGrail
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA; Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
| | - Nidhi Sahni
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, TX, USA.
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14
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Bhadhadhara K, Jani V, Koulgi S, Sonavane U, Joshi R. Studying early structural changes in SOS1 mediated KRAS activation mechanism. Curr Res Struct Biol 2023; 7:100115. [PMID: 38188543 PMCID: PMC10765296 DOI: 10.1016/j.crstbi.2023.100115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 01/09/2024] Open
Abstract
KRAS activation is known to be modulated by a guanine nucleotide exchange factor (GEF), namely, Son of Sevenless1 (SOS1). SOS1 facilitates the exchange of GDP to GTP thereby leading to activation of KRAS. The binding of GDP/GTP to KRAS at the REM/allosteric site of SOS1 regulates the activation of KRAS at CDC25/catalytic site by facilitating its exchange. Different aspects of the allosteric activation of KRAS through SOS1 are still being explored. To understand the SOS1 mediated activation of KRAS, molecular dynamics simulations for a total of nine SOS1 complexes (KRAS-SOS1-KRAS) were performed. These nine systems comprised different combinations of KRAS-bound nucleotides (GTP/GDP) at REM and CDC25 sites of SOS1. Various conformational and thermodynamic parameters were analyzed for these simulation systems. MMPBSA free energy analysis revealed that binding at CDC25 site of SOS1 was significantly low for GDP-bound KRAS as compared to that of GTP-bound KRAS. It was observed that presence of either GDP/GTP bound KRAS at the REM site of SOS1 affected the activation related changes in the KRAS present at CDC25 site. The conformational changes at the catalytic site of SOS1 resulting from GDP/GTP-bound KRAS at the allosteric changes may hint at KRAS activation through different pathways (slow/fast/rare). The allosteric effect on activation of KRAS at CDC25 site may be due to conformations adopted by switch-I, switch-II, beta2 regions of KRAS at REM site. The effect of structural rearrangements occurring at allosteric KRAS may have led to increased interactions between SOS1 and KRAS at both the sites. The SOS1 residues involved in these important interactions with KRAS at the REM site were R694, S732 and K735. Whereas the ones interacting with KRAS at CDC25 site were S807, W809 and K814. This may suggest the crucial role of these residues in guiding the allosteric activation of KRAS at CDC25 site. The conformational shifts observed in the switch-I, switch-II and alpha3 regions of KRAS at CDC25 site may be attributed to be a part of allosteric activation. The binding affinities, interacting residues and conformational dynamics may provide an insight into development of inhibitors targeting the SOS1 mediated KRAS activation.
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Affiliation(s)
- Kirti Bhadhadhara
- High Performance Computing-Medical & Bioinformatics Applications Group, Centre for Development of Advanced Computing (C-DAC), Innovation Park, Panchawati, Pashan, Pune, 411008, India
| | - Vinod Jani
- High Performance Computing-Medical & Bioinformatics Applications Group, Centre for Development of Advanced Computing (C-DAC), Innovation Park, Panchawati, Pashan, Pune, 411008, India
| | - Shruti Koulgi
- High Performance Computing-Medical & Bioinformatics Applications Group, Centre for Development of Advanced Computing (C-DAC), Innovation Park, Panchawati, Pashan, Pune, 411008, India
| | - Uddhavesh Sonavane
- High Performance Computing-Medical & Bioinformatics Applications Group, Centre for Development of Advanced Computing (C-DAC), Innovation Park, Panchawati, Pashan, Pune, 411008, India
| | - Rajendra Joshi
- High Performance Computing-Medical & Bioinformatics Applications Group, Centre for Development of Advanced Computing (C-DAC), Innovation Park, Panchawati, Pashan, Pune, 411008, India
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15
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Maujean T, Kannaboina P, Green AI, Burslem GM. Lead-oriented synthesis of epigenetic relevant scaffolds. Chem Commun (Camb) 2023; 59:14555-14558. [PMID: 37991354 PMCID: PMC10842704 DOI: 10.1039/d3cc04317g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2023]
Abstract
A simple and rational method to rank lead-likeness of molecules using continuous evaluation functions was hereby developed. This strategy proved to be competitive against known methods and finally helped in driving synthetic efforts towards candidates of interest for epigenetic applications against HDAC6, BRD4 and EZH2.
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Affiliation(s)
- Timothé Maujean
- Department of Biochemistry and Biophysics, Department of Cancer Biology and Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.
| | - Prakash Kannaboina
- Department of Biochemistry and Biophysics, Department of Cancer Biology and Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.
| | - Adam I Green
- Department of Biochemistry and Biophysics, Department of Cancer Biology and Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.
| | - George M Burslem
- Department of Biochemistry and Biophysics, Department of Cancer Biology and Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA.
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16
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Xiao Y, Chang L, Ji H, Sun H, Song S, Feng K, Nuermaimaiti A, Halemubieke S, Mei L, Lu Z, Yan Y, Wang L. Posttranslational modifications of ACE2 protein: Implications for SARS-CoV-2 infection and beyond. J Med Virol 2023; 95:e29304. [PMID: 38063421 DOI: 10.1002/jmv.29304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 10/21/2023] [Accepted: 11/26/2023] [Indexed: 12/18/2023]
Abstract
The present worldwide pandemic of coronavirus disease 2019 (COVID-19) has highlighted the important function of angiotensin-converting enzyme 2 (ACE2) as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry. A deeper understanding of ACE2 could offer insights into the mechanisms of SARS-CoV-2 infection. While ACE2 is subject to regulation by various factors in vivo, current research in this area is insufficient to fully elucidate the corresponding pathways of control. Posttranslational modification (PTM) is a powerful tool for broadening the variety of proteins. The PTM study of ACE2 will help us to make up for the deficiency in the regulation of protein synthesis and translation. However, research on PTM-related aspects of ACE2 remains limited, mostly focused on glycosylation. Accordingly, a comprehensive review of ACE2 PTMs could help us better understand the infection process and provide a basis for the treatment of COVID-19 and beyond.
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Affiliation(s)
- Yingzi Xiao
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
| | - Le Chang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
| | - Huimin Ji
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
| | - Huizhen Sun
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
| | - Shi Song
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
| | - Kaihao Feng
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
| | - Abudulimutailipu Nuermaimaiti
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
| | - Shana Halemubieke
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
| | - Ling Mei
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
| | - Zhuoqun Lu
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
| | - Ying Yan
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
| | - Lunan Wang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, People's Republic of China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing, People's Republic of China
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17
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Shin DH, Jo JY, Choi M, Kim KH, Bae YK, Kim SS. Oncogenic KRAS mutation confers chemoresistance by upregulating SIRT1 in non-small cell lung cancer. Exp Mol Med 2023; 55:2220-2237. [PMID: 37779142 PMCID: PMC10618295 DOI: 10.1038/s12276-023-01091-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/09/2023] [Accepted: 07/04/2023] [Indexed: 10/03/2023] Open
Abstract
Kirsten rat sarcoma viral oncogene homologue (KRAS) is a frequent oncogenic driver of solid tumors, including non-small cell lung cancer (NSCLC). The treatment and outcomes of KRAS-mutant cancers have not been dramatically revolutionized by direct KRAS-targeted therapies because of the lack of deep binding pockets for specific small molecule inhibitors. Here, we demonstrated that the mRNA and protein levels of the class III histone deacetylase SIRT1 were upregulated by the KRASMut-Raf-MEK-c-Myc axis in KRASMut lung cancer cells and in lung tumors of a mouse model with spontaneous KrasG12D expression. KRASMut-induced SIRT1 bound to KRASMut and stably deacetylated KRASMut at lysine 104, which increased KRASMut activity. SIRT1 knockdown (K/D) or the SIRT1H363Y mutation increased KRASMut acetylation, which decreased KRASMut activity and sensitized tumors to the anticancer effects of cisplatin and erlotinib. Furthermore, in KrasG12D/+;Sirt1co/co mice, treatment with cisplatin and erlotinib robustly reduced the tumor burden and increased survival rates compared with those in spontaneous LSL-KrasG12D/+;Sirt1+/+ mice and mice in each single-drug treatment group. Then, we identified p300 as a KRASMut acetyltransferase that reinforced KRASMut lysine 104 acetylation and robustly decreased KRASMut activity. KRASMut lysine 104 acetylation by p300 and deacetylation by SIRT1 were confirmed by LC‒MS/MS. Consistent with this finding, the SIRT1 inhibitor EX527 suppressed KRASMut activity, which synergistically abolished cell proliferation and colony formation, as well as the tumor burden in KRASMut mice, when combined with cisplatin or erlotinib. Our data reveal a novel pathway critical for the regulation of KRASMut lung cancer progression and provide important evidence for the potential application of SIRT1 inhibitors and p300 activators for the combination treatment of KRASMut lung cancer patients.
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Affiliation(s)
- Dong Hoon Shin
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
- Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
| | - Jeong Yeon Jo
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
- Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Minyoung Choi
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Kyung-Hee Kim
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
- Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Young-Ki Bae
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Sang Soo Kim
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
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18
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Wu D, Li Y, Zheng L, Xiao H, Ouyang L, Wang G, Sun Q. Small molecules targeting protein-protein interactions for cancer therapy. Acta Pharm Sin B 2023; 13:4060-4088. [PMID: 37799384 PMCID: PMC10547922 DOI: 10.1016/j.apsb.2023.05.035] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/28/2023] [Accepted: 05/22/2023] [Indexed: 10/07/2023] Open
Abstract
Protein-protein interactions (PPIs) are fundamental to many biological processes that play an important role in the occurrence and development of a variety of diseases. Targeting the interaction between tumour-related proteins with emerging small molecule drugs has become an attractive approach for treatment of human diseases, especially tumours. Encouragingly, selective PPI-based therapeutic agents have been rapidly advancing over the past decade, providing promising perspectives for novel therapies for patients with cancer. In this review we comprehensively clarify the discovery and development of small molecule modulators of PPIs from multiple aspects, focusing on PPIs in disease, drug design and discovery strategies, structure-activity relationships, inherent dilemmas, and future directions.
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Affiliation(s)
- Defa Wu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Yang Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Lang Zheng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Huan Xiao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Liang Ouyang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Guan Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Qiu Sun
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China
- West China Medical Publishers, West China Hospital, Sichuan University, Chengdu 610041, China
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19
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Miller-Phillips L, Collisson EA. RAS and Other Molecular Targets in Pancreatic Cancer: The Next Wave Is Coming. Curr Treat Options Oncol 2023:10.1007/s11864-023-01096-x. [PMID: 37296367 DOI: 10.1007/s11864-023-01096-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2023] [Indexed: 06/12/2023]
Abstract
OPINION STATEMENT Since the discovery of oncogenes in the 1970s, cancer doctors and researchers alike have understood the promise of discovering drugs to block the dominantly acting function of mutated signaling proteins in cancer. This promise was delivered, first slowly, with early signals inhibiting HER2 and BCR-Abl in the 1990s and 2000s, and then quickly, with kinase inhibitors being approved hand over fist in non-small cell lung cancer, melanoma, and many other malignancies. The RAS proteins, however, remained recalcitrant to chemical inhibition for decades, despite being, by far, the most frequently mutated oncogenes in cancers of all types. Nowhere was this deficit more palpable than in pancreatic ductal adenocarcinoma (PDA), where > 90% of cases are driven by single nucleotide substitutions at a single codon of the KRAS gene. The ice began to crack in 2012 when Ostrem and colleagues (Nature 503(7477): 548-551, 2013) synthesized the first KRAS G12C inhibitors, which covalently bind to GDP-bound G12C-mutated KRAS and lock the oncoprotein in its inactive state. In the last decade, the scientific community has established a new foundation on this and other druggable pockets in mutant KRAS. Here we provide an up-to-date overview of drugs targeting KRAS and other molecular targets in pancreatic cancer.
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Affiliation(s)
- Lisa Miller-Phillips
- Division of Hematology and Oncology, Department of Medicine and Helen Diller Family Comprehensive Cancer Center, UCSF, 1450 3Rd Street HD-375, San Francisco, CA, 94158-0128, USA
| | - Eric A Collisson
- Division of Hematology and Oncology, Department of Medicine and Helen Diller Family Comprehensive Cancer Center, UCSF, 1450 3Rd Street HD-375, San Francisco, CA, 94158-0128, USA.
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20
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Gurreri E, Genovese G, Perelli L, Agostini A, Piro G, Carbone C, Tortora G. KRAS-Dependency in Pancreatic Ductal Adenocarcinoma: Mechanisms of Escaping in Resistance to KRAS Inhibitors and Perspectives of Therapy. Int J Mol Sci 2023; 24:9313. [PMID: 37298264 PMCID: PMC10253344 DOI: 10.3390/ijms24119313] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/18/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in oncology because of its increasing incidence and poor survival rate. More than 90% of PDAC patients are KRAS mutated (KRASmu), with KRASG12D and KRASG12V being the most common mutations. Despite this critical role, its characteristics have made direct targeting of the RAS protein extremely difficult. KRAS regulates development, cell growth, epigenetically dysregulated differentiation, and survival in PDAC through activation of key downstream pathways, such as MAPK-ERK and PI3K-AKT-mammalian target of rapamycin (mTOR) signaling, in a KRAS-dependent manner. KRASmu induces the occurrence of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) and leads to an immunosuppressive tumor microenvironment (TME). In this context, the oncogenic mutation of KRAS induces an epigenetic program that leads to the initiation of PDAC. Several studies have identified multiple direct and indirect inhibitors of KRAS signaling. Therefore, KRAS dependency is so essential in KRASmu PDAC that cancer cells have secured several compensatory escape mechanisms to counteract the efficacy of KRAS inhibitors, such as activation of MEK/ERK signaling or YAP1 upregulation. This review will provide insights into KRAS dependency in PDAC and analyze recent data on inhibitors of KRAS signaling, focusing on how cancer cells establish compensatory escape mechanisms.
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Affiliation(s)
- Enrico Gurreri
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy; (E.G.); (A.A.); (G.P.); (G.T.)
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77025, USA; (G.G.); (L.P.)
| | - Giannicola Genovese
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77025, USA; (G.G.); (L.P.)
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77025, USA
- David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77025, USA
- Translational Research to Advance Therapeutics and Innovation in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77025, USA
| | - Luigi Perelli
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77025, USA; (G.G.); (L.P.)
| | - Antonio Agostini
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy; (E.G.); (A.A.); (G.P.); (G.T.)
| | - Geny Piro
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy; (E.G.); (A.A.); (G.P.); (G.T.)
| | - Carmine Carbone
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy; (E.G.); (A.A.); (G.P.); (G.T.)
| | - Giampaolo Tortora
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, 00168 Rome, Italy; (E.G.); (A.A.); (G.P.); (G.T.)
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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21
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Yuan T, Wu R, Wang W, Liu Y, Kong W, Yang B, He Q, Zhu H. Synergistic antitumor activity of regorafenib and rosuvastatin in colorectal cancer. Front Pharmacol 2023; 14:1136114. [PMID: 37138847 PMCID: PMC10149949 DOI: 10.3389/fphar.2023.1136114] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
Abstract
Introduction: Colorectal cancer is one of the most prevalent life-threatening malignant tumors with high incidence and mortality. However, the efficacy of current therapeutic regimens is very limited. Regorafenib has been approved for second- or third-line treatment of patients who are refractory to standard chemotherapy diagnosed with metastatic colorectal cancer, but its clinical efficacy needs to be further improved. Accumulating evidence demonstrates that statins also possess potent anticancer activities. However, whether regorafenib and statins pose synergistic anticancer effects in colorectal cancer is still unclear. Methods: Sulforhodamine B (SRB) assays were applied to evaluate the anti-proliferative activity of regorafenib or/and rosuvastatin in vitro, and immunoblotting analysis were applied to detect the effects of regorafenib/rosuvastatin combined treatment on mitogen-activated protein kinase (MAPK) signaling and apoptosis-related proteins. MC38 tumors were applied to investigate the synergistic anticancer effects of regorafenib in combination with rosuvastatin in vivo. Results: We found that regorafenib in combination with rosuvastatin exerted significant synergistic inhibition against colorectal cancer growth in vitro and in vivo. Mechanistically, regorafenib and rosuvastatin combination synergistically suppressed MAPK signaling, a crucial signaling pathway promoting cell survival, as indicated by the reduction of phosphorylated MEK/ERK. In addition, regorafenib in combination with rosuvastatin synergistically induced the apoptosis of colorectal cancer in vitro and in vivo. Discussion: Our study demonstrated the synergistic anti-proliferative and pro-apoptotic effects of regorafenib/rosuvastatin combined treatment in colorectal cancer in vitro/vivo and might potentially be evaluated as a novel combination regimen for clinical treatment of colorectal cancer.
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Affiliation(s)
- Tao Yuan
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Ruilin Wu
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Weihua Wang
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yue Liu
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Wencheng Kong
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bo Yang
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qiaojun He
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
- Cancer Center of Zhejiang University, Hangzhou, China
| | - Hong Zhu
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Cancer Center of Zhejiang University, Hangzhou, China
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Hong Zhu,
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22
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Wang YF, Zhao LN, Geng Y, Yuan HF, Hou CY, Zhang HH, Yang G, Zhang XD. Aspirin modulates succinylation of PGAM1K99 to restrict the glycolysis through NF-κB/HAT1/PGAM1 signaling in liver cancer. Acta Pharmacol Sin 2023; 44:211-220. [PMID: 35835856 PMCID: PMC9813364 DOI: 10.1038/s41401-022-00945-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/16/2022] [Indexed: 01/18/2023]
Abstract
Aspirin as a chemopreventive agent is able to restrict the tumor growth. Phosphoglycerate mutase 1 (PGAM1) is a key enzyme of glycolysis, playing an important role in the development of cancer. However, the underlying mechanism by which aspirin inhibits the proliferation of cancer cells is poorly understood. This study aims to identify the effects of aspirin on modulating PGAM1 enzymatic activities in liver cancer. Here, we found that aspirin attenuated the PGAM1 succinylation to suppress the PGAM1 enzymatic activities and glycolysis in hepatoma cells. Mechanically, aspirin remarkably reduced the global succinylation levels of hepatoma cells, including the PGAM1 succinylation, which led to the block of conversion from 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG) in cells. Interestingly, RNA-seq analysis identified that aspirin could significantly decrease the levels of histone acetyltransferase 1 (HAT1), a writer of PGAM1 succinylation, in liver cancer. As a target of aspirin, NF-κB p65 could effectively up-regulate the expression of HAT1 in the system, resulting in the increase of PGAM1 enzymatic activities. Moreover, we observed that the PGAM1-K99R mutant failed to rescue the aspirin-induced inhibition of PGAM1 activities, glycolysis, and proliferation of hepatoma cells relative to PGAM1-WT. Functionally, aspirin down-regulated HAT1 and decreased the PGAM1 succinylation levels in the tumor tissues from mice treated with aspirin in vivo. Thus, we conclude that aspirin modulates PGAM1K99 succinylation to restrict the PGAM1 activities and glycolysis through NF-κB p65/HAT1/PGAM1 signaling in liver cancer. Our finding provides new insights into the mechanism by which aspirin inhibits glycolysis in hepatocellular carcinoma.
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Affiliation(s)
- Yu-Fei Wang
- Department of Cancer Research, College of Life Sciences, Nankai University, Weijin Road 94, Tianjin, 300071, China
| | - Li-Na Zhao
- Department of Cancer Research, College of Life Sciences, Nankai University, Weijin Road 94, Tianjin, 300071, China
| | - Yu Geng
- Department of Cancer Research, College of Life Sciences, Nankai University, Weijin Road 94, Tianjin, 300071, China
| | - Hong-Feng Yuan
- Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, China
| | - Chun-Yu Hou
- Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, China
| | - Hui-Hui Zhang
- Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, China
| | - Guang Yang
- Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, China.
| | - Xiao-Dong Zhang
- Department of Cancer Research, College of Life Sciences, Nankai University, Weijin Road 94, Tianjin, 300071, China.
- Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhu Xi Road, Tiyuan Bei, Hexi District, Tianjin, 300060, China.
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23
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Toulany M. Targeting K-Ras-mediated DNA damage response in radiation oncology: Current status, challenges and future perspectives. Clin Transl Radiat Oncol 2022; 38:6-14. [PMID: 36313934 PMCID: PMC9596599 DOI: 10.1016/j.ctro.2022.10.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/06/2022] [Accepted: 10/08/2022] [Indexed: 11/06/2022] Open
Abstract
Approximately 60% of cancer patients receive curative or palliative radiation. Despite the significant role of radiotherapy (RT) as a curative approach for many solid tumors, tumor recurrence occurs, partially because of intrinsic radioresistance. Accumulating evidence indicates that the success of RT is hampered by activation of the DNA damage response (DDR). The intensity of DDR signaling is affected by multiple parameters, e.g., loss-of-function mutations in tumor suppressor genes, gain-of-function mutations in protooncogenes as well as radiation-induced alterations in signal-transduction pathways. Therefore, the response to irradiation differs in tumors of different types, which makes the individualization of RT as a rational but challenging goal. One contributor to tumor cell radiation survival is signaling through the Ras pathway. Three RAS genes encode 4 Ras isoforms: K-Ras4A, K-Ras4B, H-Ras, and N-Ras. RAS family members are found to be mutated in approximately 19% of human cancers. Mutations in RAS lead to constitutive activation of the gene product and activation of multiple Ras-dependent signal-transduction cascades. Preclinical studies have shown that the expression of mutant KRAS affects DDR and increases cell survival after irradiation. Approximately 70% of RAS mutations occur in KRAS. Thus, applying targeted therapies directly against K-Ras as well as K-Ras upstream activators and downstream effectors might be a tumor-specific approach to overcome K-Ras-mediated RT resistance. In this review, the role of K-Ras in the activation of DDR signaling will be summarized. Recent progress in targeting DDR in KRAS-mutated tumors in combination with radiochemotherapy will be discussed.
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AIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis. Nat Commun 2022; 13:2572. [PMID: 35546148 PMCID: PMC9095880 DOI: 10.1038/s41467-022-30149-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 04/14/2022] [Indexed: 12/11/2022] Open
Abstract
Recent development of the chemical inhibitors specific to oncogenic KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) mutants revives much interest to control KRAS-driven cancers. Here, we report that AIMP2-DX2, a variant of the tumor suppressor AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), acts as a cancer-specific regulator of KRAS stability, augmenting KRAS-driven tumorigenesis. AIMP2-DX2 specifically binds to the hypervariable region and G-domain of KRAS in the cytosol prior to farnesylation. Then, AIMP2-DX2 competitively blocks the access of Smurf2 (SMAD Ubiquitination Regulatory Factor 2) to KRAS, thus preventing ubiquitin-mediated degradation. Moreover, AIMP2-DX2 levels are positively correlated with KRAS levels in colon and lung cancer cell lines and tissues. We also identified a small molecule that specifically bound to the KRAS-binding region of AIMP2-DX2 and inhibited the interaction between these two factors. Treatment with this compound reduces the cellular levels of KRAS, leading to the suppression of KRAS-dependent cancer cell growth in vitro and in vivo. These results suggest the interface of AIMP2-DX2 and KRAS as a route to control KRAS-driven cancers. Direct targeting of oncogenic KRAS activity is a challenge. Here the authors report that a splice variant of AIMP2, AIMP2-DX2, enhances KRAS stability by blocking ubiquitin-mediated degradation of KRAS via the E3 ligase, Smurf2, and identify a chemical that can hinder AIMP2-DX2 from interacting with KRAS.
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25
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Xu Q, Zhang G, Liu Q, Li S, Zhang Y. Inhibitors of the GTPase KRAS G12C in cancer: a patent review (2019-2021). Expert Opin Ther Pat 2022; 32:475-505. [PMID: 35062845 DOI: 10.1080/13543776.2022.2032648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 01/19/2022] [Indexed: 12/19/2022]
Abstract
INTRODUCTION KRAS is one of the most important oncology proteins, which can activate multiple downstream signaling pathways. Despite the prevalence of KRAS mutations in approximately 30% of human cancers, it has long been considered to be 'undruggable' due to the lack of recognizable binding pockets. AREAS COVERED This review covers the recent patents (2019-2021) on KRASG12C inhibitors, which are mostly highlighted in terms of chemical structures, molecular mechanisms of action, pharmacokinetic properties, and potential clinical applications. EXPERT OPINION The last 3 years have seen a significant breakthrough in the development of KRAS inhibitors. So far, ten compounds entered the clinical trials with AMG510 being approved by FDA in May 2021 for the treatment of lung cancer. Moreover, MRTX849 also holds the promise of becoming the next approved drug targeting KRASG12C. However, it is noteworthy that acquired resistance is expected to arise inevitably. With a potentially effective treatment on the horizon, combination strategies could further enhance the efficacy of KRAS-targeted inhibition. Whatever their strengths or limitations, emerging KRASG12C inhibitors will undoubtedly enrich our understanding of KRAS biology and KRAS-targeted therapy, which will shed light on the development of inhibitors targeting other KRAS mutations.
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Affiliation(s)
- Qifu Xu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, 250012, RP China
| | - Guozhen Zhang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, 250012, RP China
| | - Qian Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, 250012, RP China
| | - Shunda Li
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, 250012, RP China
| | - Yingjie Zhang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, 250012, RP China
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26
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Pan S, Chen R. Pathological implication of protein post-translational modifications in cancer. Mol Aspects Med 2022; 86:101097. [PMID: 35400524 PMCID: PMC9378605 DOI: 10.1016/j.mam.2022.101097] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 02/07/2023]
Abstract
Protein post-translational modifications (PTMs) profoundly influence protein functions and play crucial roles in essentially all cell biological processes. The diverse realm of PTMs and their crosstalk is linked to many critical signaling events involved in neoplastic transformation, carcinogenesis and metastasis. The pathological roles of various PTMs are implicated in all aspects of cancer hallmark functions, cancer metabolism and regulation of tumor microenvironment. Study of PTMs has become an important area in cancer research to understand cancer biology and discover novel biomarkers and therapeutic targets. With a limited scope, this review attempts to discuss some PTMs of high frequency with recognized importance in cancer biology, including phosphorylation, acetylation, glycosylation, palmitoylation and ubiquitination, as well as their implications in clinical applications. These protein modifications are among the most abundant PTMs and profoundly implicated in carcinogenesis.
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Lu F, Shen SH, Wu S, Zheng P, Lin K, Liao J, Jiang X, Zeng G, Wei D. Hypomethylation-induced prognostic marker zinc finger DHHC-type palmitoyltransferase 12 contributes to glioblastoma progression. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:334. [PMID: 35434031 PMCID: PMC9011314 DOI: 10.21037/atm-22-520] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/16/2022] [Indexed: 12/18/2022]
Abstract
Background Glioma is the most common intracranial primary malignancy, characterized by abnormal signal transductions caused by transcriptional and post-transcriptional regulators. Studies show the palmitoylation of oncoproteins and tumor suppressors participate in cancer progression, while studies of protein S-palmitoyltransferases in glioma are limited. A systematic analysis of zinc finger DHHC-type palmitoyltransferases (ZDHHC) in glioma is still lacking. Methods A prognostic heatmap and Kaplan-Meier overall survival plot of 24 members of the ZDHHC family in pan-cancer created. The expression and prognostic significance of ZDHHC12 was analyzed by using Gene Expression Profiling Interactive Analysis (GEPIA) and PrognoScan. DBTRG and U251 cells with silenced ZDHHC12 expression were constructed and used for cell counting kit-8 (CCK-8), Transwell assay and wound healing assay in vitro. Results Here, we first conducted expression and prognostic analyses of 24 ZDHHCs from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and other glioma datasets. We found ZDHHC12 to be the only unfavorable prognostic marker in glioma. The function of ZDHHC12 in glioma was then investigated with loss-of-function strategies and in vitro cell assays. Results showed that ZDHHC12 knockdown remarkably reduced the growth, migration, and invasion capabilities in DBTRG and U251 cell lines, suggesting that ZDHHC12 may contribute to malignant behavior in glioma cells. Finally, the molecular basis for ZDHHC12 expression in glioma was analyzed, and DNA hypomethylation was found to be responsible for increased ZDHHC12 mRNA expression and related prognoses. Conclusions ZDHHC12 positively promoted the proliferation and migration of glioma cells. Decreased DNA methylation may lead to increased ZDHHC12 expression in gliomas. This study may deepen the understanding of glioma progression and therapeutics.
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Affiliation(s)
- Feng Lu
- Department of Neurosurgery, Fujian Provincial Hospital South Branch, Fuzhou, China.,Department of Neurosurgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Shang-Hang Shen
- Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, China
| | - Shizhong Wu
- Department of Neurosurgery, Fujian Provincial Hospital South Branch, Fuzhou, China.,Department of Neurosurgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Pengfeng Zheng
- Department of Neurosurgery, Fujian Provincial Hospital South Branch, Fuzhou, China.,Department of Neurosurgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Kun Lin
- Department of Neurosurgery, Fujian Provincial Hospital South Branch, Fuzhou, China.,Department of Neurosurgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Jingwei Liao
- Department of Neurosurgery, Fujian Provincial Hospital South Branch, Fuzhou, China.,Department of Neurosurgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Xiaohang Jiang
- Department of Neurosurgery, Fujian Provincial Hospital South Branch, Fuzhou, China.,Department of Neurosurgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Guangming Zeng
- Department of Neurosurgery, Fujian Provincial Hospital South Branch, Fuzhou, China.,Department of Neurosurgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - De Wei
- Department of Neurosurgery, Fujian Provincial Hospital South Branch, Fuzhou, China.,Department of Neurosurgery, Fujian Provincial Hospital, Fuzhou, China.,Department of Neurosurgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
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Tatli O, Dinler Doganay G. Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy. Molecules 2021; 26:molecules26247561. [PMID: 34946644 PMCID: PMC8703923 DOI: 10.3390/molecules26247561] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/09/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022] Open
Abstract
Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers.
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Affiliation(s)
- Ozge Tatli
- Department of Molecular Biology, Genetics-Biotechnology, Graduate School, Istanbul Technical University, Istanbul 34469, Turkey;
- Department of Molecular Biology and Genetics, Istanbul Medeniyet University, Istanbul 34720, Turkey
| | - Gizem Dinler Doganay
- Department of Molecular Biology, Genetics-Biotechnology, Graduate School, Istanbul Technical University, Istanbul 34469, Turkey;
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
- Correspondence: ; Tel.: +90-2122-857-256
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29
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Bannoura SF, Uddin MH, Nagasaka M, Fazili F, Al-Hallak MN, Philip PA, El-Rayes B, Azmi AS. Targeting KRAS in pancreatic cancer: new drugs on the horizon. Cancer Metastasis Rev 2021; 40:819-835. [PMID: 34499267 PMCID: PMC8556325 DOI: 10.1007/s10555-021-09990-2] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023]
Abstract
Kirsten Rat Sarcoma (KRAS) is a master oncogene involved in cellular proliferation and survival and is the most commonly mutated oncogene in all cancers. Activating KRAS mutations are present in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases and are implicated in tumor initiation and progression. Although KRAS is a critical oncogene, and therefore an important therapeutic target, its therapeutic inhibition has been very challenging, and only recently specific mutant KRAS inhibitors have been discovered. In this review, we discuss the activation of KRAS signaling and the role of mutant KRAS in PDAC development. KRAS has long been considered undruggable, and many drug discovery efforts which focused on indirect targeting have been unsuccessful. We discuss the various efforts for therapeutic targeting of KRAS. Further, we explore the reasons behind these obstacles, novel successful approaches to target mutant KRAS including G12C mutation as well as the mechanisms of resistance.
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Affiliation(s)
- Sahar F Bannoura
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Md Hafiz Uddin
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Misako Nagasaka
- Division of Hematology/Oncology, Department of Medicine, UCI Health, Orange, CA, 92868, USA
| | - Farzeen Fazili
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Mohammed Najeeb Al-Hallak
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Bassel El-Rayes
- Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA
| | - Asfar S Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
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Wang L, Qian J, Yang Y, Gu C. Novel insights into the impact of the SUMOylation pathway in hematological malignancies (Review). Int J Oncol 2021; 59:73. [PMID: 34368858 PMCID: PMC8360622 DOI: 10.3892/ijo.2021.5253] [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: 04/29/2021] [Accepted: 07/26/2021] [Indexed: 12/17/2022] Open
Abstract
The small ubiquitin-like modifier (SUMO) system serves an important role in the regulation of protein stability and function. SUMOylation sustains the homeostatic equilibrium of protein function in normal tissues and numerous types of tumor. Accumulating evidence has revealed that SUMO enzymes participate in carcinogenesis via a series of complex cellular or extracellular processes. The present review outlines the physiological characteristics of the SUMOylation pathway and provides examples of SUMOylation participation in different cancer types, including in hematological malignancies (leukemia, lymphoma and myeloma). It has been indicated that the SUMO pathway may influence chromosomal instability, cell cycle progression, apoptosis and chemical drug resistance. The present review also discussed the possible relationship between SUMOylation and carcinogenic mechanisms, and evaluated their potential as biomarkers and therapeutic targets in the diagnosis and treatment of hematological malignancies. Developing and investigating inhibitors of SUMO conjugation in the future may offer promising potential as novel therapeutic strategies.
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Affiliation(s)
- Ling Wang
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
| | - Jinjun Qian
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Ye Yang
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
| | - Chunyan Gu
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210022, P.R. China
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Nair VV, Yin G, Zhang J, Hancock JF, Campbell SL, Gorfe AA. Monoubiquitination of KRAS at Lysine104 and Lysine147 Modulates Its Dynamics and Interaction with Partner Proteins. J Phys Chem B 2021; 125:4681-4691. [PMID: 33929846 DOI: 10.1021/acs.jpcb.1c01062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
KRAS, a 21 kDa guanine nucleotide-binding protein that functions as a molecular switch, plays a key role in regulating cellular growth. Dysregulation of this key signaling node leads to uncontrolled cell growth, a hallmark of cancer cells. KRAS undergoes post-translational modification by monoubiquitination at various locations, including at lysine104 (K104) and lysine147 (K147). Previous studies have suggested that K104 stabilizes helix-2/helix-3 interactions and K147 is involved in nucleotide binding. However, the impact of monoubiquitination at these residues on the overall structure, dynamics, or function of KRAS is not fully understood. In this study, we examined KRAS monoubiquitination at these sites using data from extensive (12 μs aggregate time) molecular dynamics simulations complemented by nuclear magnetic resonance spectroscopy data. We found that ubiquitin forms dynamic nonspecific interactions with various regions of KRAS and that ubiquitination at both sites modulates conformational fluctuations. In both cases, ubiquitin samples a broad range of conformational space and does not form long-lasting noncovalent contacts with KRAS but it adopts several preferred orientations relative to KRAS. To examine the functional impact of these preferred orientations, we performed a systematic comparison of the dominant configurations of the ubiquitin/KRAS simulated complex with experimental structures of KRAS bound to regulatory and effector proteins as well as a model membrane. Results from these analyses suggest that conformational selection and population shift may minimize the deleterious effects of KRAS ubiquitination at K104 and K147 on binding to some but not all interaction partners. Our findings thus provide new insights into the steric effects of ubiquitin and suggest a potential avenue for therapeutic targeting.
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Affiliation(s)
- Vinay V Nair
- Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas 77030, United States.,MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas 77030, United States
| | - Guowei Yin
- Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.,The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, Guangdong, China
| | - Jerry Zhang
- Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - John F Hancock
- Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas 77030, United States.,MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas 77030, United States
| | - Sharon L Campbell
- Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, United States
| | - Alemayehu A Gorfe
- Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas 77030, United States.,MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas 77030, United States
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László L, Kurilla A, Takács T, Kudlik G, Koprivanacz K, Buday L, Vas V. Recent Updates on the Significance of KRAS Mutations in Colorectal Cancer Biology. Cells 2021; 10:667. [PMID: 33802849 PMCID: PMC8002639 DOI: 10.3390/cells10030667] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/03/2021] [Accepted: 03/10/2021] [Indexed: 12/17/2022] Open
Abstract
The most commonly mutated isoform of RAS among all cancer subtypes is KRAS. In this review, we focus on the special role of KRAS mutations in colorectal cancer (CRC), aiming to collect recent data on KRAS-driven enhanced cell signalling, in vitro and in vivo research models, and CRC development-related processes such as metastasis and cancer stem cell formation. We attempt to cover the diverse nature of the effects of KRAS mutations on age-related CRC development. As the incidence of CRC is rising in young adults, we have reviewed the driving forces of ageing-dependent CRC.
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Affiliation(s)
- Loretta László
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Anita Kurilla
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Tamás Takács
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Gyöngyi Kudlik
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Kitti Koprivanacz
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - László Buday
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
- Department of Medical Chemistry, Semmelweis University Medical School, 1071 Budapest, Hungary
| | - Virag Vas
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
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