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Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance

Acta Pharmaceutica Sinica B 2022年第4期12卷 1871-1884页

作者： Hong Wang Qianqian Wang Guodi Cai Zhijian Duan Zoann Nugent Jie Huang Jianwei Zheng Alexander D.Borowsky Jian Jian Li Peiqing Liu Hsing-Jien Kung Leigh Murphy Hong-Wu Chen Junjian Wang School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China Department of Biochemistry and Molecular Medicine University of CaliforniaDavisSacramentoCA 95817USA Research Institute in Oncology and Hematology University of Manitoba and CancerCare ManitobaWinnipeg R3E 0V9Canada Guangdong Lung Cancer Institute Guangdong Provincial Key Laboratory of Translational Medicine in Lung CancerGuangdong Provincial People’s Hospital and Guangdong Academy of Medical SciencesGuangzhou 510080China Department of Pathology and Laboratory Medicine University of CaliforniaDavisSacramentoCA 95817USA Department of Radiation Oncology University of CaliforniaDavisSacramentoCA 95817USA National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat-sen UniversityGuangzhou 510006China UC Davis Comprehensive Cancer Center School of MedicineUniversity of CaliforniaDavisSacramentoCA 95817USA

Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance.However,their interplays are poorly understood.We report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regulator),an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2(nuclear receptor binding SET domain protein 2),is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark.Mechanistically,TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2,H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new(NSD2)and established(NQO1/2,PRDX1 and GSTM4)targets of NRF2,independent of its enzymatic activity.Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis.In addition,nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival.These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

关键词： TIGAR NSD2 NRF2 Metabolism Oxidative stress Epigenetic reprogramming therapeutic resistance Redox homeostasis

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Melanoma:Molecular genetics,metastasis,targeted therapies,immunotherapies,and therapeutic resistance

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Genes & Diseases 2022年第6期9卷 1608-1623页

作者： William Wagstaff Rimel N.Mwamba Karina Grullon Mikhayla Armstrong Piao Zhao Bryce Hendren-Santiago Kevin H.Qin Alexander J.Li Daniel A.Hu Andrew Youssef Russell R.Reid Hue H.Luu Le Shen Tong-Chuan He Rex C.Haydon The Pritzker School of Medicine and the Medical Scientist Training ProgramThe University of Chicago Medical CenterChicagoIL 60637USA Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Department of Orthopaedic Surgery The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA Department of Surgery The University of Chicago Medical CenterChicagoIL 60637USA

Cutaneous melanoma is a common cancer and cases have steadily increased since the mid 70s.For some patients,early diagnosis and surgical removal of melanomas is lifesaving,while other patients typically turn to molecular targeted therapies and immunotherapies as treatment options.Easy sampling of melanomas allows the scientific community to identify the most prevalent mutations that initiate melanoma such as the BRAF,NRAS,and TERT genes,some of which can be therapeutically targeted.Though initially effective,many tumors acquire resistance to the targeted therapies demonstrating the need to investigate compensatory pathways.Immunotherapies represent an alternative to molecular targeted therapies.However,inter-tumoral immune cell populations dictate initial therapeutic response and even tumors that responded to treatment develop resistance in the long term.As the protocol for combination therapies develop,so will our scientific understanding of the many pathways at play in the progression of melanoma.The future direction of the field may be to find a molecule that connects all of the pathways.Meanwhile,noncoding RNAs have been shown to play important roles in melanoma development and progression.Studying noncoding RNAs may help us to understand how resistance e both primary and acquired e develops;ultimately allow us to harness the true potential of current therapies.This review will cover the basic structure of the skin,the mutations and pathways responsible for transforming melanocytes into melanomas,the process by which melanomas metastasize,targeted therapeutics,and the potential that noncoding RNAs have as a prognostic and treatment tool.

关键词： BRAF inhibitors Checkpoint inhibitors Drug resistance Immunotherapy Melanoma Melanoma metastasis Skin cancer Targeted therapy therapeutic resistance

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Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer

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World Journal of Gastroenterology 2023年第13期29卷 1911-1941页

作者： Sheng-Nan Ren Zhan-Yi Zhang Rui-Jie Guo Da-Ren Wang Fang-Fang Chen Xue-Bo Chen Xue-Dong Fang Nanomedicine and Translational Research Center China-Japan Union Hospital of Jilin UniversityChangchun 130033Jilin ProvinceChina Bethune Third Clinical Medical College Jilin UniversityChangchun 130021Jilin ProvinceChina Department of Gastrointestinal Colorectal and Anal SurgeryChina-Japan Union Hospital of Jilin UniversityChangchun 130033Jilin ProvinceChina

Colorectal cancer(CRC)is the most common digestive malignancy across the world.Its first-line treatments applied in the routine clinical setting include surgery,chemotherapy,radiotherapy,targeted therapy,and immunotherapy.However,resistance to therapy has been identified as the major clinical challenge that fails the treatment method,leading to recurrence and distant metastasis.An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance of CRC cells to different therapies,which can be summarized into two aspects:(1)The intrinsic characters and adapted alterations of CRC cells before and during treatment that regulate the drug metabolism,drug transport,drug target,and the activation of signaling pathways;and(2)the suppressive features of the tumor microenvironment(TME).To combat the issue of therapeutic resistance,effective strategies are warranted with a focus on the restoration of CRC cells’sensitivity to specific treatments as well as reprogramming impressive TME into stimulatory conditions.To date,nanotechnology seems promising with scope for improvement of drug mobility,treatment efficacy,and reduction of systemic toxicity.The instinctive advantages offered by nanomaterials enable the diversity of loading cargoes to increase drug concentration and targeting specificity,as well as offer a platform for trying the combination of different treatments to eventually prevent tumor recurrence,metastasis,and reversion of therapy resistance.The present review intends to summarize the known mechanisms of CRC resistance to chemotherapy,radiotherapy,immunotherapy,and targeted therapy,as well as the process of metastasis.We have also emphasized the recent application of nanomaterials in combating therapeutic resistance and preventing metastasis either by combining with other treatment approaches or alone.In summary,nanomedicine is an emerging technology with potential for CRC treatment;hence,efforts should be devoted to targeting cancer cells for the restoration of therapeuti

关键词： Colorectal cancer therapeutic resistance Nanotechnology Drug delivery system Combined treatment

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Cancer stem cells: a target for overcoming therapeutic resistance and relapse

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Cancer Biology & Medicine 2023年第12期20卷 985-1020页

作者： Shuo Zhang Rui Yang Yujie Ouyang Yang Shen Lanlin Hu Chuan Xu Department of Radiation Oncology Radiation Oncology Key Laboratory of Sichuan ProvinceSichuan Clinical Research Center for CancerSichuan Cancer Hospital&InstituteSichuan Cancer CenterAffiliated Cancer Hospital of University of Electronic Science and Technology of ChinaChengdu 610042China Department of Ultrasound in Medicine Chengdu Wenjiang District People’s HospitalChengdu 611130China Acupuncture and Massage College Chengdu University of Traditional Chinese MedicineChengdu 611137China Department of Oncology&Cancer Institute Sichuan Academy of Medical Sciences and Sichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengdu 610072China Sichuan Provincial Key Laboratory for Human Disease Gene Study Department of Laboratory MedicineSichuan Academy of Medical Sciences and Sichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengdu 610072China School of Pharmacy Macao University of Science and TechnologyMacao SAR 999078China Yu-Yue Pathology Scientific Research Center Chongqing 400039China Jinfeng Laboratory Chongqing 401329China

Cancer stem cells(CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.

关键词： Cancer stem cells therapeutic resistance metabolism immunology biomarkers

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Role of exosomes in metastasis and therapeutic resistance in esophageal cancer

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World Journal of Gastroenterology 2023年第42期29卷 5699-5715页

作者： Xing-Yu Ning Jin-Hu Ma Wei He Jun-Ting Ma The Second School of Clinical Medicine Anhui Medical UniversityHefei 230032Anhui ProvinceChina School of Basic Medical Sciences Anhui Medical UniversityHefei 230032Anhui ProvinceChina

Esophageal cancer(EC)has a high incidence and mortality rate and is emerging as one of the most common health problems globally.Owing to the lack of sensitive detection methods,uncontrollable rapid metastasis,and pervasive treatment resistance,EC is often diagnosed in advanced stages and is susceptible to local recurrence.Exosomes are important components of intercellular communication and the exosome-mediated crosstalk between the cancer and surrounding cells within the tumor microenvironment plays a crucial role in the metastasis,progression,and therapeutic resistance of EC.Considering the critical role of exosomes in tumor pathogenesis,this review focused on elucidating the impact of exosomes on EC metastasis and therapeutic resistance.Here,we summarized the relevant signaling pathways involved in these processes.In addition,we discussed the potential clinical applications of exosomes for the early diagnosis,prognosis,and treatment of EC.

关键词： Exosomes Esophageal cancer Tumor microenvironment Metastasis Signaling pathway therapeutic resistance

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Cancer-associated fibroblasts as accomplices to confer therapeutic resistance in cancer

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Cancer Drug resistance 2022年第4期5卷 889-901页

作者： Wenyu Wang Bing Cheng Qiang Yu Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease The Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510655GuangdongChina Guangdong Research Institute of Gastroenterology The Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510655GuangdongChina Cancer Precision Medicine Genome Institute of SingaporeAgency for ScienceTechnologyand ResearchBiopolisSingapore 138672Singapore Department of Physiology Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117597Singapore Cancer and Stem Cell Biology DUKE-NUS Graduate Medical School of SingaporeSingapore 169857Singapore.

The “seed and soil” concept has reformed paradigms for cancer treatment in the past decade. Accumulatingevidence indicates that the intimate crosstalk between cancer cells and stromal cells plays a tremendous role intumor progression. Cancer-associated fibroblasts (CAFs), the largest population of stroma cells, influencetherapeutic effects through diverse mechanisms. Herein, we summarize the recent advances in the versatilefunctions of CAFs regarding their heterogeneity, and we mainly discuss the pro-tumorigenic functions of CAFswhich promote tumorigenesis and confer therapeutic resistance to tumors. Targeting CAFs is emerging as one ofthe most appealing strategies in anticancer therapies. The endeavors to target or reprogram the specific subtypesof CAFs provide great cancer treatment opportunities, which may provide a better clinical benefit to cancerpatients.

关键词： Cancer-associated fibroblasts(CAFs) heterogeneity therapeutic resistance CAFs targeting

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Pancreatic cancer: genetics, disease progression, therapeutic resistance and treatment strategies

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Journal of Cancer Metastasis and Treatment 2021年第1期7卷 794-808页

作者： Karnika Singh Gauri Shishodia Hari K.Koul Department of Radiation Oncology The Ohio State University Comprehensive Cancer CenterColumbusOH 43210USA Department of Otolaryngology/Head&Neck Cancer Surgery LSU Health Sciences CenterShreveportLA 71103USA Department of Biochemistry&Molecular Biology Urology and Stanley S Scott Cancer Center School of Medicine LSU Health Sciences CenterNew OrleansLA 70112USA.

Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States.It has a very low five-year survival rate(<5%)in the United States as well as in the world(about 9%).The ... 详细信息

Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States.It has a very low five-year survival rate(resistance and surgical resection also provides only selective benefit.Signature mutations in pancreatic cancer confer chemoresistance by deregulating the cell cycle and promoting anti-apoptotic mechanisms.The stroma-rich tumor microenvironment impairs drug delivery and promotes tumor-specific immune escape.All these factors render the current treatment incompetent and prompt an urgent need for new,improved therapy.In this review,we have discussed the genetics of pancreatic cancer and its role in tumor evolution and treatment resistance.We have also evaluated new treatment strategies for pancreatic cancer,like targeted therapy and immunotherapy.

关键词： Pancreatic cancer signature mutations gemcitabine desmoplasia therapeutic resistance immunotherapy

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When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance

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Cancer Communications 2018年第1期38卷 499-510页

作者： Ching-Ying Kuo David K.Ann Department of Clinical Laboratory Sciences and Medical Biotechnology College of MedicineNational Taiwan UniversityTaipei 10048TaiwanChina Department of Diabetes Complications and Metabolism Diabetes and Metabolism Research InstituteBeckman Research InstituteCity of HopeDuarteCA 91010USA Irell and Manella Graduate School of Biological Sciences City of HopeDuarteCA 91010USA

The role of fatty acid metabolism,including both anabolic and catabolic reactions in cancer has gained increas-ing attention in recent years.Many studies have shown that aberrant expression of the genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes including metastasis,therapeutic resistance and relapse.Such phenotypes are also strongly associated with the presence of a small percentage of unique cells among the total tumor cell population.This distinct group of cells may have the ability to self-renew and propagate or may be able to develop resistance to cancer therapies independent of genetic alterations.Therefore,these cells are referred to as cancer stem cells/tumor-initiating cells/drug-tolerant persisters,which are often refractory to cancer treatment and difficult to target.Moreover,interconversion between cancer cells and cancer stem cells/tumor-initiating cells/drug-tolerant persisters may occur and makes treatment even more challenging.This review highlights recent findings on the relationship between fatty acid metabolism,cancer stemness and therapeutic resistance and prompts discussion about the potential mechanisms by which fatty acid metabolism regulates the fate of cancer cells and therapeutic resistance.

关键词： Fatty acid synthesis Fatty acid oxidation Fatty acid metabolism Lipogenic phenotype Cancer stem cells Tumor-initiating cells Cancer cell plasticity therapeutic resistance Drug-tolerant persisters

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CTRR-ncRNA:A Knowledgebase for Cancer Therapy resistance and Recurrence Associated Non-coding RNAs

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Genomics, Proteomics & Bioinformatics 2023年第2期21卷 292-299页

作者： Tong Tang Xingyun Liu Rongrong Wu Li Shen Shumin Ren Bairong Shen Institutes for Systems Genetics Frontiers Science Centre for Disease-related Molecular NetworkWest China HospitalSichuan UniversityChengdu 610041China West China School of Medicine Sichuan UniversityChengdu 610041China

Cancer therapy resistance and recurrence(CTRR)are the dominant causes of death in cancer patients.Recent studies have indicated that non-coding RNAs(ncRNAs)can not only reverse the resistance to cancer therapy but also are crucial biomarkers for the evaluation and prediction of CTRR.Herein,we developed CTRR-ncRNA,a knowledgebase of CTRR-associated ncRNAs,aiming to provide an accurate and comprehensive resource for research involving the association between CTRR and ncRNAs.Compared to most of the existing cancer databases,CTRRncRNA is focused on the clinical characterization of cancers,including cancer subtypes,as well as survival outcomes and responses to personalized therapy of cancer patients.Information pertaining to biomarker ncRNAs has also been documented for the development of personalized CTRR prediction.A user-friendly interface and several functional modules have been incorporated into the database.Based on the preliminary analysis of genotype-phenotype relationships,universal ncRNAs have been found to be potential biomarkers for CTRR.The CTRR-ncRNA is a translation-oriented knowledgebase and it provides a valuable resource for mechanistic investigations and explainable artificial intelligence-based modeling.

关键词： Translational bioinformatics therapeutic resistance Cancer recurrence Non-coding RNA Knowledgebase

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Molecular modulation of autophagy: New venture to target resistant cancer stem cells

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World Journal of Stem Cells 2020年第5期12卷 303-322页

作者： Harpreet K Mandhair Miroslav Arambasic Urban Novak Ramin Radpour Department for BioMedical Research University of BernBern 3008Switzerland Department of Medical Oncology InselspitalBern University HospitalUniversity of BernBern 3008Switzerland

Autophagy is a highly regulated catabolic process in which superfluous,damaged organelles and other cytoplasmic constituents are delivered to the lysosome for clearance and the generation of macromolecule substrates during basal or stressed conditions.Autophagy is a bimodal process with a context dependent role in the initiation and the development of cancers.For instance,autophagy provides an adaptive response to cancer stem cells to survive metabolic stresses,by influencing disease propagation via modulation of essential signaling pathways or by promoting resistance to chemotherapeutics.Autophagy has been implicated in a cross talk with apoptosis.Understanding the complex interactions provides an opportunity to improve cancer therapy and the clinical outcome for the cancer patients.In this review,we provide a comprehensive view on the current knowledge on autophagy and its role in cancer cells with a particular focus on cancer stem cell homeostasis.

关键词： Autophagy Cancer stem cells Cancer cells Cancer therapy therapeutic resistance Cancer metastasis

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