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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 *** is best known to sense high cellular ADP or AMP levels,which indicate the depletion of energy *** studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic *** this study,we report that AMPK is also highly sensitive to extracellular matrix(ECM)*** 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 *** regulation of AMPK requires the Hippo kinases but not LKB1/*** kinases directly phosphorylate AMPKa at Thr172 to activate AMPK at low ECM ***,we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma(PDAC)with high ECM stiffness and is associated with a poor survival *** activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC ***,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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A ribosomal gene panel predicting a novel synthetic lethality in non-BRCAness tumors

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Signal Transduction and Targeted Therapy 2023年第6期8卷 3070-3086页

作者： Chao Zhang Qiang Guo Lifeng Chen Zheming Wu Xiao-Jian Yan Chengyang Zou Qiuxue Zhang Jiahong Tan Tian Fang Qunxian Rao Yang Li Shizhen Shen Min Deng Liewei Wang Huanyao Gao Jia Yu Hu Li Cheng Zhang somaira nowsheen Jake Kloeber Fei Zhao Ping Yin Chunbo Teng Zhongqiu Lin Kun Song Shuzhong Yao Liangqing Yao Lingying Wu Yong Zhang Xiaodong Cheng Qinglei Gao Jian Yuan Zhenkun Lou Jin-San Zhang Beijing Institute of Basic Medical Sciences 100850BeijingChina Department of Oncology Mayo ClinicRochesterMN55905USA School of Pharmaceutical Sciences Wenzhou Medical University325035WenzhouZhejiangChina Key Laboratory of Endocrine Gland Diseases of Zhejiang Province Zhejiang Provincial People’s Hospital310014HangzhouZhejiangChina Department of Gynecology Zhejiang Provincial People’s Hospital310014HangzhouZhejiangChina Department of Gynecology the First Affiliated Hospital of Wenzhou Medical University325000WenzhouZhejiangChina Wuhan Kingwise Biotechnology Co. Ltd.430206WuhanHubeiChina Cancer Biology Research Center(Key Laboratory of the Ministry of Education) Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology430030WuhanHubeiChina Department of Gynecological Oncology Sun Yat-sen Memorial HospitalSun Yat-sen University510120GuangzhouGuangdongChina Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Reproductive Health Research 310006HangzhouZhejiangChina Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases 310006HangzhouZhejiangChina Department of Molecular Pharmacology and Experimental Therapeutics Mayo ClinicRochesterMN55905USA Department of Dermatology University of California San DiegoSan DiegoCA92122USA Key Laboratory of Saline-alkali Vegetation Ecology Restoration Ministry of EducationCollege of Life ScienceNortheast Forestry University150040HarbinChina Division of Gynecology Oncology Department of Obstetrics and GynecologyQilu HospitalShandong University250012JinanShandongChina Department of Obstetrics and Gynecology the First Affiliated HospitalSun Yat-Sen University510080GuangzhouGuangdongChina Department of Gynecologic Oncology Obstetrics and Gynecology Hospital of Fudan University200090ShanghaiChina Department of Gynecologic Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of

Poly(ADP-ribose)polymerase(PARP)inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination(HR)***,many patients without apparent HR defects also respond well to PARP inhibitors/*** biomarker responsible for this mechanism remains ***,we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient *** inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage(ATM)signaling-induced pro-apoptotic ribosomal stress,which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA ***,the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/*** gene panel as an independent biomarker was validated by multiple published clinical datasets,as well as by an ovarian cancer organoids library we *** importantly,its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS ***,we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell *** drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired ***,our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy.

关键词： drugs BRCA panel

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