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Fantastic voyage: The journey of NLRP3 inflammasome activation

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Genes & Diseases 2024年第2期11卷 819-829页

作者： Xiangyong Que Sihao Zheng Qibin Song Huadong Pei Pingfeng Zhang Cancer Center Renmin Hospital of Wuhan UniversityWuhanHubei 430060China Department of oncology Georgetown Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashingtonDC 20057USA

NLRP3 inflammasome,an intracellular multiprotein complex,can be activated by a range of pathogenic microbes or endogenous hazardous chemicals.Its activation results in the release of cytokines such as IL-1β and IL-18,as well as Gasdermin D which eventually causes pyroptosis.The activation of NLRP3 inflammasome is under strict control and regulation by numerous pathways and mechanisms.Its excessive activation can lead to a persistent inflammatory response,which is linked to the onset and progression of severe illnesses.Recent studies have revealed that the subcellular localization of NLRP3 changes significantly during the activation process.In this review,we review the current understanding of the molecular mechanism of NLRP3 inflammasome activation,focusing on the subcellular localization of NLRP3 and the associated regulatory mechanisms.We aim to provide a comprehensive understanding of the dynamic transportation,activation,and degradation processes of NLRP3.

关键词： Inflammasome activation Innate immunity NLRP3 NLRP3 inflammasome Subcellular localization

Systematic pan-cancer analysis reveals OGT and OGA as potential biomarkers for tumor microenvironment and therapeutic responses

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Genes & Diseases 2024年第4期11卷 1-4页

作者： Chunyan Hou Ci Wu Wenge Zhu Huadong Pei Junfeng Ma Department of oncology Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonDC 20007USA Department of Biochemistry and Molecular Medicine School of Medicine and Health ScienceGeorge Washington UniversityWashingtonDC20052USA

Protein O-linkedβ-N-acetylglucosamine(O-GlcNAc)modification(O-GlcNAcylation)is a unique monosaccharide modification of essential importance in physiology and pathology.1,2 As a highly dynamic process,O-GlcNAcylation is mediated by two paired enzymes:O-GlcNAc transferase(OGT)and O-GlcNAcase(OGA),which add or remove the modification from proteins,respectively.Emerging evidence demonstrates that the aberrant O-GlcNAcylation underlies the initiation,progression,and metastasis of cancer.

关键词： metastasis pathology therapeutic

Recent advances and remaining challenges in lung cancer therapy

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Chinese Medical Journal 2024年第5期137卷 533-546页

作者： Tasha Barr Shoubao Ma Zhixin Li Jianhua Yu Department of Hematology and Hematopoietic Cell Transplantation City of Hope National Medical CenterLos AngelesCalifornia 91010USA comprehensive Cancer Center City of HopeLos AngelesCalifornia 91010USA Department of Immuno-oncology Beckman Research InstituteLos AngelesCalifornia 91010USA

Lung cancer remains the most common cause of cancer death.Given the continued research into new drugs and combination therapies,outcomes in lung cancer have been improved,and clinical benefits have been expanded to a broader patient population.However,the overall cure and survival rates for lung cancer patients remain low,especially in metastatic cases.Among the available lung cancer treatment options,such as surgery,radiation therapy,chemotherapy,targeted therapies,and alternative therapies,immunotherapy has shown to be the most promising.The exponential progress in immuno-oncology research and recent advancements made in the field of immunotherapy will further increase the survival and quality of life for lung cancer patients.Substantial progress has been made in targeted therapies using tyrosine kinase inhibitors and monoclonal antibody immune checkpoint inhibitors with many US Food And Drug Administration(FDA)-approved drugs targeting the programmed cell death ligand-1 protein(e.g.,durvalumab,atezolizumab),the programmed cell death-1 receptor(e.g.,nivolumab,pembrolizumab),and cytotoxic T-lymphocyte-associated antigen 4(e.g.,tremelimumab,ipilimumab).Cytokines,cancer vaccines,adoptive T cell therapies,and Natural killer cell mono-and combinational therapies are rapidly being studied,yet to date,there are currently none that are FDA-approved for the treatment of lung cancer.In this review,we discuss the current lung cancer therapies with an emphasis on immunotherapy,including the challenges for future research and clinical applications.

关键词： Lung cancer Therapy Immunotherapy Combination therapy Adoptive T cell therapies

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CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

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Cellular & Molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling Colin A.Chavel Anand P.Sharda Mackenzie M.Lieberman Caitlin M.James Shivana M.Lightman Jason H.Tong Guanxi Qiao Tiffany R.Emmons Thejaswini Giridharan Shengqi Hou Andrew M.Intlekofer Richard M.Higashi Teresa W.M.Fan Andrew N.Lane Kevin H.Eng Brahm H.Segal Elizabeth A.Repasky Kelvin P.Lee Scott H.Olejniczak Department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Department of Medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA Department of Cancer Genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Present address:University of Colorado Boulder BoulderCO 80309USA Present address:Dana Farber Cancer Institute BostonMA 02215USA Present address:Massachusetts Institute of Technology BostonMA 02139USA Present address:Melvin and Bren Simon comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202USA

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 PKM2

Emerging mechanisms of ferroptosis and its implications in lung cancer

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中华医学杂志(英文版) 2024年第7期137卷 818-829页

作者： Li Qian Song Qibin Pei Huadong Chen Yali USA State Key Laboratory of Medical Proteomics National Center for Protein Sciences (Beijing) Beijing Institute of Lifeomics Beijing 102206 Cancer Center Renmin Hospital of Wuhan University Wuhan Hubei 430060 China Department of oncology Georgetown Lombardi comprehensive Cancer Center Georgetown University Medical Center Washington D.C. 20057

Lung cancer is one of the most common malignancies and has the highest number of deaths among all cancers. Despite continuous advances in medical strategies, the overall survival of lung cancer patients is still low, probably due to disease progression or drug resistance. Ferroptosis is an iron-dependent form of regulated cell death triggered by the lethal accumulation of lipid peroxides, and its dysregulation is implicated in cancer development. Preclinical evidence has shown that targeting the ferroptosis pathway could be a potential strategy for improving lung cancer treatment outcomes. In this review, we summarize the underlying mechanisms and regulatory networks of ferroptosis in lung cancer and highlight ferroptosis-targeting preclinical attempts to provide new insights for lung cancer treatment.

关键词： Lung cancer Ferroptosis Ferroptosis regulators Ferroptosis inducers Cancer treatment

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

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World Journal of Gastroenterology 2024年第13期30卷 1815-1835页

作者： Samantha Sharma Naresh Singh Anita Ahmed Turk Isabella Wan Akshay Guttikonda Julia Lily Dong Xinna Zhang Mateusz Opyrchal Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN 46202United States Division of Hematology/oncology Department of MedicineIndiana University School of MedicineIndianapolisIN 46202United States Melvin and Bren Simon comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202United States

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

关键词： Colorectal cancer Immune checkpoint inhibitors Clinical trials Immunotherapy Microsatellite instability Microsatellite stability DNA mismatch repair

Evidence-Based Dampness-Heat ZHENG(Syndrome) in Cancer: Current Progress toward Establishing Relevant Animal Model with Pancreatic Tumor

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Chinese Journal of Integrative Medicine 2024年第1期30卷 85-95页

作者： JIAO Ju-ying CHENG Chien-shan CAO Zhang-qi CHEN Lian-yu CHEN Zhen Department of Integrative oncology Fudan University Shanghai Cancer CenterShanghai(200032)China Department of oncology Shanghai Medical CollegeFudan UniversityShanghai(200032)China

Cancer is one of the deadliest diseases affecting the health of human beings. With limited therapeutic options available, complementary and alternative medicine has been widely adopted in cancer management and is increasingly becoming accepted by both patients and healthcare workers alike. Chinese medicine characterized by its unique diagnostic and treatment system is the most widely applied complementary and alternative medicine. It emphasizes symptoms and ZHENG(syndrome)-based treatment combined with contemporary disease diagnosis and further stratifies patients into individualized medicine subgroups. As a representative cancer with the highest degree of malignancy, pancreatic cancer is traditionally classified into the "amassment and accumulation". Emerging perspectives define the core pathogenesis of pancreatic cancer as "dampness-heat" and the respective treatment "clearing heat and resolving dampness" has been demonstrated to prolong survival in pancreatic cancer patients, as has been observed in many other cancers. This clinical advantage encourages an exploration of the essence of dampness-heat ZHENG(DHZ) in cancer and investigation into underlying mechanisms of action of herbal formulations against dampness-heat. However, at present, there is a lack of understanding of the molecular characteristics of DHZ in cancer and no standardized and widely accepted animal model to study this core syndrome in vivo. The shortage of animal models limits the ability to uncover the antitumor mechanisms of herbal medicines and to assess the safety profile of the natural products derived from them. This review summarizes the current research on DHZ in cancer in terms of the clinical aspects, molecular landscape, and animal models. This study aims to provide comprehensive insight that can be used for the establishment of a future standardized ZHENG-based cancer animal model.

关键词： cancer Chinese medicine syndrome ZHENG dampness-heat syndrome animal model pancreatic tumor evaluation methods

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Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer

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Chinese Medical Journal 2024年第3期137卷 338-349页

作者： Feng Xu Kun Xu Lingling Fan Xintong Li Yiqiu Liu Fang Yang Chengjun Zhu Xiaoxiang Guan Department of oncology The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China Department of oncology Jiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityJiangsu Institute of Cancer ResearchNanjingJiangsu 210009China The comprehensive Cancer Center of Nanjing Drum Tower Hospital Affiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu 210008China Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Personalized Cancer MedicineNanjing Medical UniversityNanjingJiangsu 211166China

Background:Triple-negative breast cancer(TNBC)is an aggressive type of breast cancer associated with poor prognosis and limited treatment options.The androgen receptor(AR)has emerged as a potential therapeutic target for luminal androgen receptor(LAR)TNBC.However,multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits.This study aimed to investigate the role of AR in TNBC and its detailed mechanism.Methods:Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4(NECTIN4)expression in TNBC tissues.Then,in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta(ERβ)in TNBC.Chromatin immunoprecipitation sequencing(ChIP-seq),co-immunoprecipitation(co-IP),molecular docking method,and luciferase reporter assay were performed to identify key molecules that affect the function of AR.Results:Based on the TNBC tissue array analysis,we revealed that ERβand AR were positive in 21.92%(32/146)and 24.66%(36/146)of 146 TNBC samples,respectively,and about 13.70%(20/146)of TNBC patients were ERβpositive and AR positive.We further demonstrated the pro-tumoral effects of AR on TNBC cells,however,the oncogenic biology was significantly suppressed when ERβtransfection in LAR TNBC cell lines but not in AR-negative TNBC.Mechanistically,we identified that NECTIN4 promoter–42 bp to–28 bp was an AR response element,and that ERβinteracted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression.Conclusions:This study suggests that ERβfunctions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation.Therefore,our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

关键词： Androgen receptor Estrogen receptor beta Triple-negative breast cancer NECTIN4 Oncogenic effects Tumor progression

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Mechanism of PARP inhibitor resistance and potential overcoming strategies

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Genes & Diseases 2024年第1期11卷 306-320页

作者： Xiaoyu Fu Ping Li Qi Zhou Ruyuan He Guannan Wang Shiya Zhu Amir Bagheri Gary Kupfer Huadong Pei Juanjuan Li Department of oncology Georgetown Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashingtonDC 20057USA Department of Breast and Thyroid Surgery Renmin Hospital of Wuhan UniversityWuhanHubei 430060China Cancer Center Renmin Hospital of Wuhan UniversityWuhanHubei 430060China Department of Thoracic Surgery Renmin Hospital of Wuhan UniversityWuhanHubei 430060China

PARP inhibitors(PARPi)are a kind of cancer therapy that targets poly(ADP-ribose)polymerase.PARPi is the first clinically approved drug to exert synthetic lethality by obstruct-ing the DNA single-strand break repair process.Despite the significant therapeutic effect in pa-tients with homologous recombination(HR)repair deficiency,innate and acquired resistance to PARPi is a main challenge in the clinic.In this review,we mainly discussed the underlying mechanisms of PARPi resistance and summarized the promising solutions to overcome PARPi resistance,aiming at extending PARPi application and improving patient outcomes.

关键词： Drug resistance Homologous recombination PARP PARP inhibitor Poly(ADP-ribose)polymerase