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Boosting synergism of chemo- and immunotherapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

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Acta Pharmaceutica Sinica B 2024年第2期14卷 836-853页

作者： Ge Song Minghui Li Shumin Fan Mengmeng Qin Bin Shao Wenbing Dai Hua Zhang Xueqing Wang Bing He Qiang Zhang Beijing key laboratory of Molecular Pharmaceutics and New Drug Delivery Systems School of Pharmaceutical SciencesPeking UniversityBeijing 100191China state key laboratory of natural and biomimetic drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Medical Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer HospitalBeijing 100142China

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs.It is critical to inspire new potential to remodel the value of this classical therapeutic strategy.Here,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic drugs.Alendronate in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle core.The synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic mechanism.Differing from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy.Therefore,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

关键词： Bisphosphonate coordinationlipid nanogranules Ferroptosis Mevalonatemetabolism Mitochondrial metabolism Nano-systematic biology

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Immunology reshapes neuroscience,and neuroscience reshapes immunology

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Fundamental research 2024年第2期4卷 199-200页

作者： Bo Peng Yanxia Rao Yun Wang Shumin Duan Hai Qi Jing Yang Hongliang Zhang Department of Neurosurgery Huashan HospitalInstitute for Translational Brain ResearchState Key Laboratory of Medical NeurobiologyMOE Frontiers Center for Brain ScienceMOE Innovative Center for New Drug Development of Immune Inflammatory DiseasesFudan UniversityShanghai 200040China Department of laboratory Animal Science MOE Frontiers Center for Brain ScienceFudan UniversityShanghai 200032China Neuroscience research Institute and Department of Neurobiology School of Basic Medical SciencesKey Laboratory for NeuroscienceMinistry of Education/National Health Commission and State Key Laboratory of Natural and Biomimetic DrugsPeking UniversityBeijing 100083China PKU-IDG/McGovern Institute for Brain research Peking UniversityBeijing 100871China Faculty of Medicine and Pharmaceutical Sciences Zhejiang UniversityHangzhou 310014China School of Medicine Tsinghua UniversityBeijing 100084China IDG/McGovern Institute for Brain research Center for Life SciencesSchool of Life SciencesPeking UniversityBeijing 100871China Chinese Institute for Brain research Beijing 102206China Department of Life Sciences National Natural Science Foundation of ChinaBeijing 100085China

As a result of evolution,our body has evolved into a sophisticated system in which various tissues and organs cooperate in a highly orchestrated manner.Few tissues or organs operate in isolation.The brain serves as the command center of our body and is relatively isolated from the peripheral system due to the presence of the blood-brain barrier(BBB).This barrier prevents direct and extensive interaction between blood cells,plasma molecules,and brain cells,contributing to the longstanding perception of the brain as an“immune-privileged”area.Consequently,neuroscientists and immunologists historically conducted separate research with minimal overlap between these two disciplines.However,this perspective has undergone reconsideration over the past few decades.

关键词： organs overlap contributing

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LATS1 K751 acetylation blocks activation of Hippo signalling and switches LATS1 from a tumor suppressor to an oncoprotein

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Science China(Life Sciences) 2022年第1期65卷 129-141页

作者： Siyuan Yang Weizhi Xu Cheng Liu Jiaqi Jin Xueying Li Yuhan Jiang Lei Zhang Xianbin Meng Jun Zhan Hongquan Zhang Department of Human Anatomy Histology and EmbryologyMOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic DrugsPeking University Health Science CenterBeijing 100191China moe key laboratory of Bioinformatics School of Life SciencesTsinghua UniversityBeijing 100084China

Large tumor suppressor 1(LATS1)is the key kinase controlling activation of Hippo signalling pathway.Post-translational modifications of LATS1 modulate its kinase activity.However,detailed mechanism underlying LATS1 stability and activation remains elusive.Here we report that LATS1 is acetylated by acetyltransferase CBP at K751 and is deacetylated by deacetylases SIRT3 and SIRT4.Acetylation at K751 stabilized LATS1 by decreasing LATS1 ubiquitination and inhibited LATS1 activation by reducing its phosphorylation.Mechanistically,LATS1 acetylation resulted in inhibition of YAP phosphorylation and degradation,leading to increased YAP nucleus translocation and promoted target gene expression.Functionally,LATS1-K751 Q,the acetylation mimic mutant potentiated lung cancer cell migration,invasion and tumor growth,whereas LATS1-K751 R,the acetylation deficient mutant inhibited these functions.Taken together,we demonstrated a previously unidentified post-translational modification of LATS1 that converts LATS1 from a tumor suppressor to a tumor promoter by suppression of Hippo signalling through acetylation of LATS1.

关键词： LATS1 acetylation LATS1 activation and inhibition Hippo signalling pathway lung adenocarcinoma

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FERM domain-containing protein FRMD6 activates the mTOR signaling pathway and promotes lung cancer progression

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Frontiers of Medicine 2023年第4期17卷 714-728页

作者： Tianzhuo Wang Huiying Guo Lei Zhang Miao Yu Qianchen Li Jing Zhang Yan Tang Hongquan Zhang Jun Zhan Program for Cancer and Cell Biology Department of Human AnatomyHistology and EmbryologySchool of Basic Medical SciencesBeijing 100191China Peking University International Cancer Institute Beijing 100191China moe key laboratory of carcinogenesis and translational research and state key laboratory of natural and biomimetic drugs Peking University Health Science CenterBeijing 100191China

FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progression.We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues.In addition,the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma(n=75,P=0.0054)and lung adenocarcinoma(n=94,P=0.0330).Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6.Mechanistically,FRMD6 interacts and colocalizes with mTOR and S6K,which are the key molecules of the mTOR signaling pathway.FRMD6 markedly enhances the interaction between mTOR and S6K,subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells.Furthermore,knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6^(−/−)gene KO MEFs and mice.Altogether,our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.

关键词： FRMD6 lung cancer mTOR pathway

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The DNMT1-PAS1-PH20 axis drives breast cancer growth and metastasis

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Signal Transduction and Targeted Therapy 2022年第4期7卷 1311-1321页

作者： Yenan Fu Xi Zhang Xiao Liu Peng Wang Wenhui Chu Wei Zhao Yunling Wang Guangbiao Zhou Yu Yu Hongquan Zhang Program for Cancer and Cell Biology Department of Human AnatomyHistology and EmbryologySchool of Basic Medical SciencesPKU International Cancer InstituteMOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic DrugsPeking University Health Science CenterBeijing 100191China Department of Orthopedics Peking University Third HospitalBeijing 100191China Institute for Cardiovascular research Peking UniversityBeijing 100191China state key laboratory of Molecular Oncology National Cancer CenterNational Clinical Research Center for CancerCancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

PH20 is a member of the human hyaluronidase family that degrades hyaluronan in the extracellular matrix and controls tumor progression.Inhibition of DNA methyltransferases(DNMTs)leads to elevated hyaluronan levels;however,whether DNMT inhibitors control PH20 remains unclear.Here,we report that the DNMT1 inhibitor,decitabine,suppresses PH20 expression by activating the long non-coding RNA PHACTR2-AS1(PAS1).PAS1 forms a tripartite complex with the RNA-binding protein vigilin and histone methyltransferase SUV39H1.The interaction between PAS1 and vigilin maintains the stability of PAS1.Meanwhile,PAS1 recruits SUV39H1 to trigger the H3K9 methylation of PH20,resulting in its silencing.Functionally,PAS1 inhibits breast cancer growth and metastasis,at least partially,by suppressing PH20.Combination therapy of decitabine and PAS1-30nt-RNA,which directly binds to SUV39H1,effectively blocked breast cancer growth and metastasis in mice.Taken together,DNMT1,PAS1,and PH20 comprise a regulatory axis to control breast cancer growth and metastasis.These findings reveal that the DNMT1-PAS1-PH20 axis is a potential therapeutic target for breast cancer.

关键词： metastasis breast DNMT1

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Local sustained release of PD-1 monoclonal antibody and lenvatinib by thermo-sensitive hydrogel for improving tumor immunotherapy

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中国化学快报:英文版 2023年第8期34卷 241-247页

作者： Lin Zhai Yujie Shi Yi Yan An Lu Xiaoyu Liu Lei Lei Yi Sun Linxia Jiang Xiangyu Wang Honggang Qian Jiancheng Wang Beijing key laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Pharmaceutical Analysis School of Pharmaceutical SciencesPeking UniversityBeijing 100191China key laboratory of carcinogenesis and translational research(Ministry of Education) Department of Hepato-Pancreato-Biliary SurgeryPeking University Cancer Hospital&InstituteBeijing 100142China

In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenvatinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited by the problems of inconsistent pharmacokinetic profiles of two drugs,lower drug accumulation in tumor and obvious side effects during the combination therapy.Here,in situ-forming thermosensitive hydrogels based on PLGA-PEG-PLGA triblock copolymers were prepared for local administration of anti-PD1 and LEN(P&L@Gel)to improve therapeutic efficacy and safety.After peritumoral or surgical resection site injection,the significant increased concentrations of both drugs in tumor were observed with the local sustained release of P&L@Gel.In comparison with the group of intraperitoneal anti-PD1 plus oral LEN(P-ip&L-po),significantly higher tumor inhibition efficiency on CT26 tumor models could be obtained in P&L@Gel group,even at the dose of one-eighth of the former,same tumorinhibition effects could be achieved.The enhanced antitumor efficacy of P&L@Gel group was probably associated with the 2.2 folds of increased level of CD8+T cells and the polarization of tumor associated macrophage from M2 to M1 along with the increased drug accumulation.Moreover,compared with the obvious side effects of P-ip&L-po group,no significant changes of PLT,ALT and UA in blood,as well as IL-1αand IL-1βin mice paws were observed between P&L@Gel group and untreated group.These results suggested that local administration of anti-PD1 and LEN with thermosensitive hydrogel could offer a potential strategy for tumors or tumor postoperative adjuvant treatment.

关键词： Lenvatinib PD-1 antibody Thermosensitive hydrogels Topical administration Tumor immunotherapy

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Four and a half LIM domains protein 1 can be as a double-edged sword in cancer progression

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Cancer Biology & Medicine 2020年第2期17卷 270-281页

作者： Xiaofan Wei Hongquan Zhang key laboratory of carcinogenesis and translational research(Ministry of Education) Department of Human AnatomyHistology and Embryologyand State Key Laboratory of Natural and Biomimetic DrugsPeking University Health Science CenterBeijing 100191China

Four and a half LIM domains protein 1(FH L1),as the name suggests,contains four and a half LIM domains capable o f interacting with various molecules,including structural proteins,kinases,and transcriptional machinery.FHL1 contains a zinc-finger domain and performs diverse roles in regulation of gene transcription,cytoarchitecture,cell proliferation,and signal transduction.Several studies have validated the importance of FHL1 in muscle development,myopathy,and cardiovascular diseases.Mutations in the FHL1 gene are associated with various myopathies.Recently,FHL1 was identified as a major host factor for chikungunya virus(CHIKV)infection in both humans and mice.Based on more recent findings over the last decade,FHL1 is proposed to play a dual role in cancer progression.On the one hand,FHL1 expression is suppressed in several cancer types,which correlates with increased metastatic disease and decreased survival.Moreover,FHL1 is reported to inhibit tum or cell growth and migration by associating with diverse signals,such as TGF-P and ER,and therefore considered a tumor suppressor.On the other hand,FHL1 can function as an oncogenic protein that promotes tumor progression upon phosphorylation,reflecting complex roles in cancer.This review primarily focuses on the dual role and underlying mechanisms of action of FHL1 in human cancer progression and its clinical relevance.

关键词： Four and a half LIM protein 1(FH L1) metastasis tumor cell growth

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Integrin-interacting protein Kindlin-2 induces mammary tumors in transgenic mice

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Science China(Life Sciences) 2019年第2期62卷 225-234页

作者： Bing Li Xiaochun Chi Jiagui Song Yan Tang Juan Du Xiaokun He Xiaoran Sun Zhenwu Bi Yunling Wang Jun Zhan Hongquan Zhang Department of Anatomy Histology and Embryology Key Laboratory of Carcinogenesis and Translational Research Ministry of Educationand State Key Laboratory of Natural and Biomimetic Drugs Peking University Health Science Center Institute of Cardiovascular research Peking University Health Science Center

Kindlin-2, an integrin-interacting protein, regulates breast cancer progression. However, currently, no animal model to study the role of Kindlin-2 in the carcinogenesis of mammary gland is available. We established a Kindlin-2 transgenic mouse model using a mammary gland-specific promoter, mammary tumor virus(MMTV) long terminal repeat(LTR). Kindlin-2 was overexpressed in the epithelial cells of the transgenic mice. The mammary gland ductal trees were found to grow faster in MMTV-Kindlin-2 transgenic mice than in control mice during puberty. Kindlin-2 promoted mammary gland growth as indicated by more numerous duct branches and larger lumens, and more alveoli were formed in the mammary glands during pregnancy under Kindlin-2 overexpression. Importantly, mammary gland-specific expression of Kindlin-2 induced tumor formation at the age of 55 weeks on average. Additionally, the levels of estrogen receptor and progesterone receptor were decreased, whereas human epidermal growth factor receptor 2 and β-catenin were upregulated in the Kindlin-2-induced mammary tumors. These findings demonstrated that Kindlin-2 induces mammary tumor formation via activation of the Wnt signaling pathway.

关键词： Kindlin-2 breast cancer mouse mammary gland growth mammary tumorigenesis transgenic mouse

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G protein-coupled receptor LGR6 is an independent risk factor for colon adenocarcinoma

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Frontiers of Medicine 2019年第4期13卷 482-491页

作者： Wenjing Wang Shigang Ding Hejun Zhang Jun Li Jun Zhan Hongquan Zhang Department of Gastroenterology Peking University Third Hospital Beijing 100191 China key laboratory of carcinogenesis and translational research (Ministry of Education) and State Key Laboratory of Natural and Biomimetic Drugs and Department of Anatomy Histology and Embryology Peking University Health Science Center Beijing 100191 China

LGR6 is a member of the G protein-coupled receptor family that plays a tumor-suppressive role in colon cancer. However, the relationship between LGR6 expression in patients and clinicopathological factors remains unclear. This study aimed to clarify whether the expression level of LGR6 is correlated with colon adenocarcinoma progression. Immunohistochemistry was used to detect LGR6 expression in colon adenoma tissues (n = 21), colon adenocarcinoma tissues (n = 156), and adjacent normal tissues (n = 124). The expression levels of LGR6 in colon adenoma and adenocarcinoma were significantly higher than those in normal colon epithelial tissues (P < 0.001). Low LGR6 expression predicted a short overall survival in patients with colon adenocarcinoma (log-rank test, P = 0.016). Univariate and multivariate survival analyses showed that, in addition to N and M classification, LGR6 expression served as an independent prognostic factor. Thus, low expression of LGR6 can be used as an independent prognostic parameter in patients with colon adenocarcinoma.

关键词： LGR6 colon adenocarcinoma immunohistochemistry prognosis

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C1orf106, an innate immunity activator, is amplified in breast cancer and is required for basal-like/luminal progenitor fate decision

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Science China(Life Sciences) 2019年第9期62卷 1229-1242页

作者： Ji Ma Cheng Liu Decao Yang Jiagui Song Jing Zhang Tianzhuo Wang Mengyuan Wang Weizhi Xu Xueying Li Shigang Ding Jun Zhan Hongquan Zhang key laboratory of carcinogenesis and translational research (Ministry of Education) Department of AnatomyHistology and Embryologyand State Key Laboratory of Natural and Biomimetic DrugsPeking University Health Science CenterBeijing 100191China Department of Gastroenterology Peking University Third HospitalBeijing 100191China

Basal-like breast cancer with a luminal progenitor gene expression profile is an aggressive subtype of breast cancer with a poorer prognosis compared with other subtypes.However,genes that specifically promote basal-like breast cancer development remain largely unknown.Here,we report that a novel gene C1orf106 plays an important role in maintaining the feature of basal-like/luminal progenitors.C1orf106 is frequently amplified and overexpressed in basal-like breast cancer and is associated with a poor outcome in patients.In human TCGA database,C1orf106 expression was correlated with upregulation of ELF5 and downregulation of GATA3,two transcription factors that regulate mammary gland stem cell fate.Enhanced expression of C1orf106 promotes tumor progression and expression of basal-like/luminal progenitor marker ELF5;depletion of C1orf106 suppresses tumorigenesis and expression of basal-like/luminal progenitor marker GATA3.These findings suggest that C1orf106 maintains the basal-like/luminal progenitor character through balancing the expression of ELF5 and GATA3.Taken together,we demonstrated that C1orf106 is an important regulator for basal-like/luminal progenitors and targeting C1orf106 is of therapeutic value for breast cancer.

关键词： C1orf106 basal-like luminal progenitor breast cancer ELF5 GATA3

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