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Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer

Genes & Diseases 2024年第3期11卷 338-350页

作者： Xin Xu Yuan Fang Somaira Nowsheen Ye-Xiong Li Zhenkun Lou Min Deng State Key Laboratory of molecular oncology and Department of radiation oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of General Surgery Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghai 200080China Department of General Surgery Zhongshan HospitalFudan UniversityShanghai 200032China Department of Dermatology University of California San DiegoSan DiegoCA 92093USA Department of oncology Mayo ClinicRochesterMN 55905USA

The adenosine monophosphate(AMP)-activated protein kinase(AMPK)sits at a cen-tral node in the regulation of energy metabolism and tumor progression.AMPK is best known to sense high cellular ADP or AMP levels,which indicate the depletion of energy stores.Previous studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic cancer.In this study,we report that AMPK is also highly sensitive to extracellular matrix(ECM)stiffness.We found that AMPK is activated in cells when cultured under low ECM stiffness conditions and is functionally required for the metabolic switch induced by ECM stiffness.This regulation of AMPK requires the Hippo kinases but not LKB1/CaMKKp.Hippo kinases directly phosphorylate AMPKa at Thr172 to activate AMPK at low ECM stiffness.Furthermore,we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma(PDAC)with high ECM stiffness and is associated with a poor survival outcome.The activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC growth.Together,these findings establish a novel model for AMPK regulation by the mechanical properties of ECMs and provide a rationale for simultaneously targeting the ECM stiffness-Hippo kinases-AMPK signaling and low glucose-LKB1-AMPK signaling pathways as an effective therapeutic strategy against PDAC.

关键词： AMPKactivity Cellularmetabolic switch ECM stiffness Hippokinase signaling Pancreaticductal adenocarcinoma

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Overdose the addiction—A new strategy to ablate cancer cells

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Science China(Life Sciences) 2015年第11期58卷 1169-1170页

作者： LI Lei Department of Experimental radiation oncology Department of Genetics The University of Texas M.D.Anderson Cancer Center

In the field of antitumor drug development,it is common to see paired images of cultured cancer cells:one mocktreated,and the other subjected to a small molecular drug that leads to cell death or growth suppression(Figure 1).One’s common perception is that an inhibitor is at work to inactivate a critical factor or pathway essential for

关键词：癌细胞小分子药物药物开发肿瘤细胞抗肿瘤生长抑制细胞死亡细胞生存

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^(68)Gallium-labelled PSMA-PET/CT as a diagnostic and clinical decision-making tool in Asian prostate cancer patients following prostatectomy

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Cancer Biology & Medicine 2019年第1期16卷 157-165页

作者： Janice S.H.Tan Charles X.Y.Goh Yen Sin Koh Youquan Li Jeffrey K.L.Tuan Eu Tiong Chua Terence W.K.Tan Michael L.C.Wang Lui Shiong Lee Kae Jack Tay Ravindran Kanesvaran Chee Keong Toh Aaron K.T.Tong Winnie W.C.Lam Melvin L.K.Chua Division of radiation oncology National Cancer Centre Singapore Department of Nuclear Medicine and molecular Imaging Singapore General Hospital Radiological Sciences Academic Clinical Programme Duke-NUS Medical School oncology Academic Clinical Programme Duke-NUS Medical School Department of Urology Singapore General Hospital Department of Surgery Sengkang General Hospital Division of Medical oncology National Cancer Centre Singapore Division of Medical Sciences National Cancer Centre Singapore

Objective: Prostate cancers(PCa) in Asian individuals are molecularly distinct from those found in their Caucasian counterparts.There is no risk stratification tool for Asian men with rapid biochemical recurrence(BCR) following radical prostatectomy(Rad P). This study aims to assess the detection rate of ^(68)Ga-prostate-specific membrane antigen-positron emission tomography/computed tomography(PSMA-PET/CT) for diagnosis of clinical recurrence and as a treatment decision making tool in Asian patients with BCR post-Rad P.Methods: ^(68)Ga PSMA-PET and CT body with/without bone scan [conventional workup(CWU)] were performed in 55 Asian patients with BCR within 36 months post-Rad P. Two blinded reviewers assessed the images. Detection rates of ^(68)Ga PSMAPET/CT were evaluated, and impact on management was reviewed by comparison with CWU.Results: Median time to BCR post-Rad P was 8.1 months. Detection rate for ^(68)Ga PSMA-PET/CT was 80%(44/55). A positive scan was significantly associated with increasing prostate-specific antigen(PSA) level [odds ratio(OR) = 1.13(95% CI 1.05–1.30), P =0.017], but not with higher Gleason grade or shorter PSA doubling time. Compared to CWU, ^(68)Ga PSMA-PET/CT detected an additional 106 lesions in 33/44 patients with a positive scan, resulting in a change in management in 25/44(56.8%) patients: 10 to hormonal therapy(HT) and whole pelvis radiotherapy(RT) in addition to bed RT, and 15 to palliative HT alone.Conclusions: In the present report, we demonstrated the diagnostic and treatment decision utility of ^(68)Ga PSMA-PET/CT in Asian men with rapid BCR. Detection of small volume nodal and systemic recurrences at low PSA levels(< 1.0 ng/mL) highlights the role of the tool in assigning patients to treatment intensification with HT-RT or palliative HT in polymetastatic disease.

关键词： ^68Ga PSMA PET/CT prostate cancer Asian diagnostic recurrence prostatectomy salvage radiotherapy

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Gain-of-function mutant p53 in cancer progression and therapy

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Journal of molecular Cell Biology 2020年第9期12卷 674-687页

作者： Cen Zhang Juan Liu Dandan Xu Tianliang Zhang Wenwei Hu Zhaohui Feng 1Department of radiation oncology Rutgers Cancer Institute of New JerseyRutgers-State University of New JerseyNew BrunswickNJ 08903USA

p53 is a key tumor suppressor,and loss of p53 function is frequently a prerequisite for cancer development.The p53 gene is the most frequently mutated gene in human cancers;p53 mutations occur in>50%of all human cancers and in almost every type of human cancers.Most of p53 mutations in cancers are missense mutations,which produce the full-length mutant p53(mutp53)protein with only one amino acid difference from wild-type p53 protein.In addition to loss of the tumor-suppressive function of wild-type p53,many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression,termed gain-of-function(GOF).Mutp53 protein often accumulates to very high levels in cancer cells,which is critical for its GOF.Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer,therapies targeting mutp53 have attracted great interest.Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53.In this review,we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers.

关键词： tumor suppressor p53 mutation gain-of-function tumorigenesis cancer therapy

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Genetic polymorphisms in genes regulating cell death and prognosis of patients with rectal cancer receiving postoperative chemoradiotherapy

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Cancer Biology & Medicine 2023年第4期20卷 297-316页

作者： Hongxia Chen Luxi Yin Jie Yang Ningxin Ren Jinna Chen Qixuan Lu Ying Huang Yanru Feng Weihu Wang Shulian Wang Yueping Liu Yongwen Song Yexiong Li Jing Jin Wen Tan Dongxin Lin State Key Laboratory of molecular oncology Department of Etiology and CarcinogenesisBeijing Key Laboratory for Carcinogenesis and Cancer PreventionNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of radiation oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaGuangzhou 510060China

Objective:The identification of biomarkers for predicting chemoradiotherapy efficacy is essential to optimize personalized treatment.This study determined the effects of genetic variations in genes involved in apoptosis,pyroptosis,and ferroptosis on the prognosis of patients with locally advanced rectal cancer receiving postoperative chemoradiotherapy(CRT).Methods:The Sequenom MassARRAY was used to detect 217 genetic variations in 40 genes from 300 patients with rectal cancer who received postoperative CRT.The associations between genetic variations and overall survival(OS)were evaluated using hazard ratios(HRs)and 95%confidence intervals(CIs)computed using a Cox proportional regression model.Functional experiments were performed to determine the functions of the arachidonate 5-lipoxygenase(ALOX5)gene and the ALOX5 rs702365 variant.Results:We detected 16 genetic polymorphisms in CASP3,CASP7,TRAILR2,GSDME,CASP4,HO-1,ALOX5,GPX4,and NRF2 that were significantly associated with OS in the additive model(P[C]represses ALOX5 transcription and corollary experiments suggested that ALOX5 may promote colon cancer cell growth by mediating an inflammatory response.Conclusions:Polymorphisms in genes regulating cell death may play essential roles in the prognosis of patients with rectal cancer who are treated with postoperative CRT and may serve as potential genetic biomarkers for individualized treatment.

关键词： Rectal neoplasms genetic variation regulated cell death overall survival ALOX5

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基于多参数MR成像的高危肿瘤内亚区域体积预测胶质母细胞瘤总体生存期和补充分子分析

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国际医学放射学杂志 2017年第6期 730-731页

作者： Y.Cui S.J.Ren K.K.Tha J.Wu H.Shirato R.J.Li 张毓婧 Department of radiation oncology Stanford University

摘要目的通过整合多参数MR影像,建立并验证一个可预测胶质母细胞瘤预后的基于容积的定量影像学标志物,同时研究其与分子特征的关系及协同作用。方法回顾性分

关键词：胶质母细胞瘤生存期 MR 多参数

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E2FBP1 antagonizes the p16^(INK4A)-Rb tumor suppressor machinery for growth suppression and cellular senescence by regulating promyelocytic leukemia protein stability

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International Journal of Oral Science 2011年第4期3卷 200-208页

作者： Yayoi Fukuyo Akiko Takahashi Eiji Hara Nobuo Horikoshi Tej K. Pandita Takuma Nakajima Department of Immunology Tulane National Primate Research Center Section of Bacterial Pathogenesis Graduate School Tokyo Medical and Dental University Division of Cancer Biology The Cancer Institute Japanese Foundation for Cancer Research Division of molecular radiation Biology Department of Radiation Oncology University of Texas Southwestern Medical Center

Cellular senescence is an irreversible cell cycle arrest triggered by the activation of oncogenes or mitogenic signaling as well as the enforced expression of tumor suppressors such as p53, p16INK4A and promyelocytic leukemia protein （PML） in normal cells. E2F-binding protein 1 （E2FBP1）, a transcription regulator for E2F, induces PML reduction and suppresses the formation of PML-nuclear bodies, whereas the down-regulation of E2FBP1 provokes the PML-dependent premature senescence in human normal fibroblasts. Here we report that the depletion of E2FBP1 induces the accumulation of PML through the Ras-dependent activation of MAP kinase signaling. The cellular levels of p16INK4A and p53 are elevated during premature senescence induced by depletion of E2FBP1, and the depletion of p16INK4A, but not p53 rescued senescent cells from growth arrest. Therefore, the premature senescence induced by E2FBP1 depletion is achieved through the pl6INK4A-Rb pathway. Similar to human normal fibroblasts, the growth inhibition induced by E2FBP1 depletion is also observed in human tumor cells with intact p16INK4A and Rb. These results suggest that E2FBP1 functions as a critical antagonist to the pI6INK4A-Rb tumor suppressor machinery by regulating PML stability.

关键词： E2F-binding protein 1 senescence cell cycle ubiquitin promyelocytic leukemia protein

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Salicylic acid sensitizes cervical cancer cells to radiotherapy by activating AMPK/TSC2/mTOR pathway

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radiation Medicine and Protection 2022年第1期3卷 9-15页

作者： Shun Lu Wenjing Ye Jie Zhou Guangming Yi Jianming Huang Siyao Deng Minglun Li Yimin Li Yanqiong Song Jiayu Zhang Lichun Wei Guiquan Zhu Jinyi Lang Department of radiation oncology Sichuan Cancer Hospital&InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengdu 610042China Department of Radiological Protection Radiation Oncology Key Laboratory of Sichuan ProvinceChengdu 610042China School of Medicine University of Electronic Science and Technology of ChinaChengdu 610042China The Third Hospital of Mianyang Sichuan Mental Health CenterMianyangSichuan 621054China Department of radiation oncology University HospitalLMUMunichGermany Department of radiation oncology Xijing HospitalAir Force Medical UniversityXi'anShaanxi 610599China State Key Laboratory of Oral Diseases National Clinical Research Centre for Oral DiseasesDepartment of Head and Neck OncologyWest China Hospital of StomatologySichuan UniversityChengdu 610041China

Objective:To investigate the radio-sensitizing effect of salicylic acid(SA)on human cervical cancer cells and its potential molecular mechanism.Methods:Cervical cancer cells were treated with SA and ionizing radiation.The expression ofγ-H2AX was evaluated by immunofluorescence(IF)assay.Cell cycle and apoptosis were analyzed by flow cytometry.Western blot was performed to detect the protein level of AMPK/TSC2/mTOR pathway.Results:SA inhibited basal proliferation of cervical cancer cells in a dose and time dependent manner.In addition,SA increased radiation-induced DNA damage,promoted apoptosis,triggered a redistribution of cell cycle from G2-M phase to G1-S phase of cervical cancer cells,and hence increased cell sensitivity to radiation.Moreover,SA treatment elevated the expression levels of p-AMPKα(t=3.996,P<0.05)and p-TSC2(t=5.308,P<0.05),whereas the level of p-mTOR(t=10.160,P<0.05)was significantly decreased.Conclusion:SA enhances the radiosensitivity of cervical cancer cells by targeting AMPK/TSC2/mTOR signaling pathway,and might serve as a promising therapeutic strategy to improve the efficacy of radiotherapy for cervical cancer.

关键词： Cervical cancer Salicylic acid Radiosensitivity AMPK/TSC2/mTOR pathway

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Radiotherapy combined with immunotherapy:the dawn of cancer treatment

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Signal Transduction and Targeted Therapy 2022年第8期7卷 2974-3007页

作者： Zengfu Zhang Xu Liu Dawei Chen Jinming Yu Department of radiation oncology Shandong University Cancer CenterYantai RoadNo.2999JinanShandongChina Department of radiation oncology Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJiyan RoadNo.440JinanShandongChina

Radiotherapy(RT)is delivered for purposes of local control,but can also exert systemic effect on remote and non-irradiated tumor deposits,which is called abscopal effect.The view of RT as a simple local treatment has dramatically changed in recent years,and it is now widely accepted that RT can provoke a systemic immune response which gives a strong rationale for the combination of RT and immunotherapy(iRT).Nevertheless,several points remain to be addressed such as the interaction of RT and immune system,the identification of the best schedules for combination with immunotherapy(IO),the expansion of abscopal effect and the mechanism to amplify iRT.To answer these crucial questions,we roundly summarize underlying rationale showing the whole immune landscape in RT and clinical trials to attempt to identify the best schedules of iRT.In consideration of the rarity of abscopal effect,we propose that the occurrence of abscopal effect induced by radiation can be promoted to 100%in view of molecular and genetic level.Furthermore,the“radscopal effect”which refers to using low-dose radiation to reprogram the tumor microenvironment may amplify the occurrence of abscopal effect and overcome the resistance of iRT.Taken together,RT could be regarded as a trigger of systemic antitumor immune response,and with the help of IO can be used as a radical and systemic treatment and be added into current standard regimen of patients with metastatic cancer.

关键词： immunotherapy treatment rational

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Functional characterization of SAG/RBX2/ROC2/RNF7, an antioxidant protein and an E3 ubiquitin ligase

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Protein & Cell 2013年第2期4卷 103-116页

作者： Yi Sun Hua Li Division of radiation and Cancer Biology Department of Radiation OncologyUniversity of Michigan4424B Medical Science-I1301 Catherine StreetAnn ArborMI 48109USA.

SAG(Sensitive to Apoptosis Gene),also known as RBX2(RING box protein 2),ROC2(Regulator of Cullins 2),or RNF7(RING Finger Protein 7),was originally cloned in our laboratory as a redox inducible antioxi-dant protein and later characterized as the second member of the RBX/ROC RING component of the SCF(SKP1-CUL-F-box Proteins)E3 ubiquitin ligase.When acting alone,SAG scavenges oxygen radicals by forming inter-and intra-molecular disulfide bonds,whereas by forming a complex with other components of the SCF E3 ligase,SAG promotes ubiquitination and degradation of a number of protein substrates,includ-ing c-JUN,DEPTOR,HIF-1α,IκBα,NF1,NOXA,p27,and procaspase-3,thus regulating various signaling path-ways and biological processes.Specifically,SAG pro-tects cells from apoptosis,confers radioresistance,and plays an essential and non-redundant role in mouse embryogenesis and vasculogenesis.Furthermore,stress-inducible SAG is overexpressed in a number of human cancers and SAG overexpression correlates with poor patient prognosis.Finally,SAG transgenic expression in epidermis causes an early stage inhibi-tion,but later stage promotion,of skin tumorigenesis triggered by DMBA/TPA.Given its major role in pro-moting targeted degradation of tumor suppressive proteins,leading to apoptosis suppression and accel-erated tumorigenesis,SAG E3 ligase appears to be an attractive anticancer target.

关键词： antioxidant angiogenesis apoptosis Cullin-RING ligases radiation resistance reactive oxygen species SAG/RBX2/ROC2/RNF7 SCF E3 ligases tumori-genesis ubiquitin ligase vasculogenesis

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