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TLR-mediated metabolic reprogramming in the tumor microenvironment: potential novel strategies for cancer immunotherapy

中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Zhenhong Ni Jintao He Yaran Wu Xufang Dai Xiaojing Yan Bo Li Xinzhe Li Haojun Xiong Jiqin Lian Fengtian He Department of Biochemistry and Molecular Biology College of Basic Medical SciencesArmy Medical University Institute of Combined Injury College of Preventive MedicineArmy Medical University College of Educational Science Chongqing Normal University

Phosphorylation is a major type of post-translational modification,which can influence the cellular physiological ***4 B,a key autophagy-related protein,has a potential effect on the survival of tumor ***,it is still unknown as to the role of Atg4 B phosphorylation in *** this study,we identified a novel phosphorylation site at Ser34 of Atg4 B induced by AKT in hepatocellular carcinoma(HCC) *** phosphorylation of Atg4 B at Ser34 had little effect on autophagic flux,but promoted the warburg effect including the increase of L-lactate production and glucose consumption,and the decrease of oxygen consumption in HCC *** Ser34 phosphorylation of Atg4 B also contributed to the impairment of mitochondrial activity including the inhibition of F1 Fo-ATP synthase activity and the elevation of mitochondrial ROS in HCC ***,the phosphorylation of Atg4 B at Ser34 enhanced its mitochondrial location and the subsequent colocalization with F1 Fo-ATP synthase in HCC ***,recombinant human Atg4 B protein suppressed the activity of F1 Fo-ATP synthase in MgATP submitochondrial particles from patient-derived HCC tissues in *** summary,our results demonstrate for the first time that the phosphorylation of Atg4 B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function,which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of Atg4 B and the subsequent inhibition of F1 Fo-ATP synthase *** findings reveal a noncanonical working pattern of Atg4 B under pathological conditions,which may provide a scientific basis for developing novel strategies for HCC treatment by targeting Atg4 B and its Ser34 phosphorylation.

关键词： Akt Atg4B Phosphorylation warburg effect HCC

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Cellular & Molecular Immunology 2018年第5期15卷 1-10页

作者： Lan Huang Huaxi Xu Guangyong Peng Division of Infectious Diseases Allergy and ImmunologyDepartment of Internal MedicineSaint Louis University School of MedicineSaint LouisMO 63104USA Department of Microbiology and Immunology Jiangsu University School of MedicineZhenjiang 212013China Correspondence:G PengMDPhDDivision of Infectious DiseasesAllergy and ImmunologyDepartment of Internal MedicineSaint Louis University School of MedicineSaint LouisMO 63104USA.

Cellular energy metabolism not only promotes tumor cell growth and metastasis but also directs immune cell survival,proliferation and the ability to perform specific and functional immune responses within the tumor microenvironment.A better understanding of the molecular regulation of metabolism in different cell components in the tumor-suppressive microenvironment is critical for the development of effective strategies for human cancer ***-like receptors(TLRs)have recently been recognized as critical factors involved in tumor pathogenesis,regulating both tumor cells and tumor-infiltrating innate and adaptive immune ***,little is known about the molecular crosstalk between TLR signaling and tumor or/and immune cell metabolism,although there is abundant expression of TLRs in these *** this review,we explore the functional role of TLR signaling in reprogramming cell metabolism in the tumor *** particular,we discuss how malignant tumors regulate metabolism to support their growth and survival,summarize more recently identified metabolic profiles of different immune cell subsets and TLR-mediated regulation of cellular metabolism in both tumor and immune cells,and further explore potential strategies targeting cell metabolism for TLR-based cancer *** improved understanding of these issues should open new avenues for the development of novel strategies via TLR-mediated metabolic reprogramming of the tumor microenvironment for cancer immunotherapy.

关键词： checkpoint blockade immunotherapy metabolic reprogramming tumor microenvironment warburg effect

Metabolic reprogramming in triple-negative breast cancer

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Cancer Biology & Medicine 2020年第1期17卷 44-59页

作者： Zhanyu Wang Qianjin Jiang Chenfang Dong Department of Surgical Oncology(Breast Center)of The Second Affiliated Hospital Zhejiang University School of MedicineHangzhou 310058China Department of Pathology and Pathophysiology Zhejiang University School of MedicineHangzhou 310058China

Since triple-negative breast cancer(TNBC)was first defined over a decade ago,increasing studies have focused on its genetic and molecular *** diagnosed with TNBC,compared to those diagnosed with other breast cancer subtypes,have relatively poor outcomes due to high tumor aggressiveness and lack of targeted *** reprogramming,an emerging hallmark of cancer,is hijacked by TNBC to fulfill bioenergetic and biosynthetic demands;maintain the redox balance;and further promote oncogenic signaling,cell proliferation,and *** the mechanisms of metabolic remodeling may guide the design of metabolic strategies for the effective intervention of ***,we review the metabolic reprogramming of glycolysis,oxidative phosphorylation,amino acid metabolism,lipid metabolism,and other branched pathways in TNBC and explore opportunities for new biomarkers,imaging modalities,and metabolically targeted therapies.

关键词： Metabolic reprogramming triple-negative breast cancer aerobic glycolysis warburg effect cancer stem cell targeted therapy

Identification of human LDHC4 as a potential target for anticancer drug discovery

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2348-2357页

作者： Hong Tan Huali Wang Jinhu Ma Hui Deng Qinghua He Qiang Chen Qinglian Zhang The Research Institute of Qinghai-Tibet Plateau Southwest Minzu UniversityChengdu 610041China State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan Universityand Collaborative Innovation Center of BiotherapyChengdu 610041China School of Laboratory Medicine Chengdu Medical CollegeChengdu 610500China Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Southwest Minzu UniversityChengdu 610041China

One of the distinct hallmarks of cancer cells is aerobic glycolysis(warburg effect). Lactate dehydrogenase A(LDHA) is thought to play a key role in aerobic glycolysis and has been extensively studied, while lactate dehydrogenase C(LDHC), an isoform of LDHA, has received much less *** we showed that human LDHC was significantly expressed in lung cancer tissues, overexpression of Ldhc in mice could promote tumor growth, and knock-down of LDHC could inhibit the proliferation of lung cancer A549 cells. We solved the first crystal structure of human LDHC4 and found that the activesite loop of LDHC4 adopted a distinct conformation compared to LDHA4 and lactate dehydrogenase B4(LDHB4). Moreover, we found that(ethylamino)(oxo)acetic acid shows about 10 times selective inhibition against LDHC4 over LDHA4 and LDHB4. Our studies suggest that LDHC4 is a potential target for anticancer drug discovery and(ethylamino)(oxo)acetic acid provides a good start to develop lead compounds for selective drugs targeting LDHC4.

关键词： LDHC Anticancer target warburg effect LDHC4 structure (Ethylamino)(oxo)acetic acid LDH isoforms Lung cancer Tissue microarray

Deciphering the dual role and prognostic potential of PINK1 across cancer types

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Neural Regeneration Research 2021年第4期16卷 659-665页

作者： Katherine Dai Daniel P.Radin Donna Leonardi Department of Molecular Cellularand Developmental BiologyYale UniversityNew HavenCTUSA Department of Pharmacology Stony Brook University School of MedicineStony BrookNYUSA Bergen County Academies HackensackNJUSA

Metabolic rewiring and deregulation of the cell cycle are hallmarks shared by many *** mutations in key tumor suppressor genes,such as PTEN,and oncogenes predispose cancer cells for marked utilization of resources to fuel accelerated cell proliferation and chemotherapeutic *** research has demonstrated that PTEN-induced putative kinase 1(PINK1)acts as a pivotal regulator of mitochondrial homeostasis in several cancer types,a function that also extends to the regulation of tumor cell proliferative *** addition,involvement of PINK1 in modulating inflammatory responses has been highlighted by recent studies,further expounding PINK1’s multifunctional *** review discusses the oncogenic roles of PINK1 in multiple tumor cell types,with an emphasis on maintenance of mitochondrial homeostasis,while also evaluating literature suggesting a dual oncolytic mechanism based on PINK1’s modulation of the warburg *** a clinical standpoint,its expression may also dictate the response to genotoxic stressors commonly used to treat multiple *** detailing the evidence suggesting that PINK1 possesses distinct prognostic value in the clinical setting and reviewing the duality of PINK1 function in a context-dependent manner,we present avenues for future studies of this dynamic protein.

关键词： apoptosis cancer cell cycle inflammation metabolic stress mitochondral quality control mitophagy PINK1 tumor warburg effect

Structural insight into mechanisms for dynamic regulation of PKM2

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Protein & Cell 2015年第4期6卷 275-287页

作者： Ping Wang Chang Sun Tingting Zhu Yanhui Xu1 Fudan University Shanghai Cancer Center and Institute of Biomedical Sciences Shanghai Medical College of Fudano University Shanghai 200032 China State Key Laboratory of Genetic Engineering School of Life Sciences Fudan University Shanghai 200433 China

Pyruvate kinase isoform M2 （PKM2） converts phospho- enolpyruvate （PEP） to pyruvate and plays an important role in cancer metabolism. Here, we show that post- translational modifications and a patient-derived muta- tion regulate pyruvate kinase activity of PKM2 through modulating the conformation of the PKM2 tetramer. We determined crystal structures of human PKM2 mutants and proposed a ＂seesaw＂ model to illustrate confor- mational changes between an inactive T-state and an active R-state tetramers of PKM2. Biochemical and structural analyses demonstrate that PKM2^Y105E （phos- phorylation mimic of Y105） decreases pyruvate kinase activity by inhibiting FBP （fructose 1,6-bisphosphate）- induced R-state formation, and PKM2K^3305Q （acetylation mimic of K305） abolishes the activity by hindering tet- ramer formation. K422R, a patient-derived mutation of PKM2, favors a stable, inactive T-state tetramer because of strong intermolecular interactions. Our study reveals the mechanism for dynamic regulation of PKM2 by post- translational modifications and a patient-derived muta- tion and provides a structural basis for further investi- gation of other modifications and mutations of PKM2 yet to be discovered.

关键词： pyruvate kinase M2 crystal structureallosteric regulation warburg effect post-translational modifications

The reversed intra- and extracellular pH in tumors as a unified strategy to chemotherapeutic delivery using targeted nanocarriers

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Acta Pharmaceutica Sinica B 2021年第8期11卷 2243-2264页

作者： Edgar Pérez-Herrero Alberto Fernández-Medarde Departamento de Ingeniería Química y Tecnología Farmacéutica Universidad de La LagunaLa Laguna 38206TenerifeSpain Instituto Universitario de Bio-Orgánica Antonio González Universidad de La LagunaLa Laguna 38206TenerifeSpain Instituto Universitario de Tecnologías Biomédicas Universidad de La LagunaLa Laguna 38200TenerifeSpain Instituto de Biología Molecular y Celular Del Cáncer Centro de Investigación Del Cáncer(USAL-CSIC)Salamanca 37007Spain

Solid tumors are complex entities,comprising a wide variety of malignancies with very different molecular *** this,they share a set of characteristics known as"hallmarks of cancer"that can be used as common therapeutic ***,every tumor needs to change its metabolism in order to obtain the energy levels required for its high proliferative rates,and these adaptations lead to alterations in extra-and intracellular *** changes in p H are common to all solid tumors,and can be used either as therapeutic targets,blocking the cell proton transporters and reversing the pH changes,or as means to specifically deliver anticancer *** this review we will describe how proton transport inhibitors in association with nanocarriers have been designed to block the pH changes that are needed for cancer cells to survive after their metabolic *** will also describe studies aiming to decrease intracellular pH in cancer using nanoparticles as molecular cages for protons which will be released upon UV or IR light ***,we will comment on several studies that have used the extracellular pH in cancer for an enhanced cell internalization and tumor penetration of nanocarriers and a controlled drug delivery,describing how nanocarriers are being used to increase drug stability and specificity.

关键词： pH-Gradient inversion Metabolism of glucose Proton transport inhibitors Proton-caged carriers Chemotherapy Targeted drug delivery pH-Sensitive nanocarriers warburg effect Cancer

CD87-targeted BiTE and CAR-T cells potently inhibit invasive nonfunctional pituitary adenomas

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Science China(Life Sciences) 2024年第10期67卷 2169-2185页

作者： Yuan Ren Xinjie Bao Ming Feng Bing Xing Wei Lian Yong Yao Renzhi Wang Department of Neurosurgery Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China

Recently,bispecific T-cell engagers(BiTEs)and chimeric antigen receptor-modified T cells(CAR-Ts)have been shown to have high therapeutic efficacy in hematological ***87 is highly expressed in solid tumors with an oncogenic *** assess their cytotoxic effects on invasive nonfunctioning pituitary adenomas(iNFPAs),we first examined CD87 expression and its effects on the metabolism of iNFPA *** generated CD87-specific BiTE and CAR/IL-12 T cells,and their cytotoxic effects on iNFPAs cells and in mouse models were ***87 had high expression in i NFPA tissue and cell samples but was undetected in noncancerous brain ***87×CD3 BiTE and CD87 CAR/IL-12 T-cells showed antigenic specificity and exerted satisfactory cytotoxic effects,decreasing tumor cell proliferation in vitro and reducing existing tumors in experimental ***,the above findings suggest that CD87 is a promising target for the immunotherapeutic management of iNFPAs using anti-CD87 BiTE and CD87-specific CAR/IL-12 T cells.

关键词： CD87 chimeric antigen receptor T cells invasive non-functional pituitary adenomas bispecific T cell engager warburg effect

Fenton reactions drive nucleotide and ATP syntheses in cancer

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Journal of Molecular Cell Biology 2018年第5期10卷 448-459页

作者： Huiyan Sun Chi Zhang Sha Cao Tao Sheng Ning Dong Ying Xu College of Computer Science and Technology Jilin University Changchun China Computational Systems Biology Lab Department of Biochemistry and Molecular Biology and institute of Bioinformatics University of Georgia GA USA School of Public Health Jilin University Changchun China The First Hospital of Jilin University Changchun China

We present a computational study of tissue transcriptomic data of 14 cancer types to address： what may drive cancer cell division？ Our analyses point to that persistent disruption of the intraceUular pH by Fenton reactions may be at the root of cancer development. Specifically, we have statistically demonstrated that Fenton reactions take place in cancer cytosoi and mitochondria across all the 14 cancer types, based on cancer tissue gene-expression data integrated via the Michaelis-Menten equation. In addition, we have shown that （i） Fenton reactions in cytosol of the disease cells will continuously increase their pH, to which the cells respond by generating net protons to keep the pH stable through a combination of synthesizing glycolytic ATPs and consuming them by nucleotide syntheses, which may drive cell division to rid of the continuously synthesized nucleotides; and （ii） Fenton reactions in mitochondria give rise to novel ways for ATP synthesis with electrons ultimately coming from H2O2, largely originated from immune cells. A model is developed to link these to cancer development, where some mutations may be selected to facilitate cell division at rates dictated by Fenton reactions.

关键词： cancer driver Fenton reaction gene-expression data intracellular pH warburg effect