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Targeting receptor tyrosine kinases in gastric cancer

World Journal of Gastroenterology 2014年第16期20卷 4536-4545页

作者： Asahiro Morishita Jian Gong Tsutomu Masaki Department of Gastroenterology and Neurology Kagawa University School of MedicineKagawa 761-0793Japan

Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials.One group of representative targeted oncogenic kinases,the receptor tyrosine kinases(RTKs),has been associated with gastric cancer development.Trastuzumab,an inhibitor of ERBB2,has been approved for the treatment of gastric cancer,although other receptor tyrosine kinases,such as epidermal growth factor receptor,vascular endothelial growth factor,platelet-derived growth factor receptor,c-Met,IGF-1R and fibroblast growth factor receptor 2,are also activated in gastric cancer.The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients.On the other hand,the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients;however,a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial.Other clinical trials,especially phaseⅢtrials that have tested drugs targeting RTKs,such as cetuximab,panitumumab,gefitinib,erlotinib,figitumumab,sorafenib,sunitinib and lapatinib,have shown that these drugs have modest effects against gastric cancer.This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.

关键词： Receptor tyrosine kinases Gastric cancer Epidermal

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Group Ⅱ p21-activated kinases as therapeutic targets in gastrointestinal cancer

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World Journal of Gastroenterology 2016年第3期22卷 1224-1235页

作者： Yang-Guang Shao Ke Ning Feng Li Department of Cell Biology Key Laboratory of Cell BiologyMinistry of Public Health and Key Laboratory of Medical Cell BiologyMinistry of EducationChina Medical University

P21-activated kinases(PAKs) are central players in various oncogenic signaling pathways. The six PAK family members are classified into group Ⅰ(PAK1-3) and group Ⅱ(PAK4-6). Focus is currently shifting from group Ⅰ PAKs to group Ⅱ PAKs. Group Ⅱ PAKs play important roles in many fundamental cellular processes, some of which have particular significance in the development and progression of cancer. Because of their important functions, group Ⅱ PAKs have become popular potential drug target candidates. However, few group Ⅱ PAKs inhibitors have been reported, and most do not exhibit satisfactory kinase selectivity and "drug-like" properties. Isoform- and kinase-selective PAK inhibitors remain to be developed. This review describes the biological activities of group Ⅱ PAKs, the importance of group Ⅱ PAKs in the development and progression of gastrointestinal cancer, and smallmolecule inhibitors of group Ⅱ PAKs for the treatment of cancer.

关键词： Group Ⅱ p21-activated kinases Signalingpathway Gastrointestinal cancer PAK4 inhibitor Drugtarget

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Aurora kinases: novel anti-breast cancer targets

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Oncology and Translational Medicine 2019年第1期5卷 43-48页

作者： Yiliyaer Yusufu Maimaiti Xinjiang Medical University Graduate School People's Hospital of Xinjiang Uygur Autonomous Region

Aurora kinases regulate multiple steps of mitotic cell division in eukaryotic cells. Overexpression of aurora kinases has been observed in some tumor cells, which suggests that abnormalities in aurora kinases are closely related to tumorigenesis. In additon, aurora kinases are often amplified or overexpressed in breast cancer cells, leading to chromosomal segregation abnormalities and genomic disorder, and thereby activating oncogenic pathways. Novel Aurora A kinase inhibitors are currently being studied in multiple phase I and II studies. In this review, we describe the biological functions and mechanisms of aurora kinases in breast cancer cells and summarize the preclinical findings related to aurora kinases in breast cancer.

关键词： aurora kinases breast cancer inhibitors

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The role of Src family kinases in mediating M-CSF receptor signaling and monocytic cell survival

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Advances in Bioscience and Biotechnology 2012年第5期3卷 592-602页

作者： Yijie Wang Melissa G. Piper Clay B. Marsh Department of Internal Medicine Division of Pulmonary Allergy Critical Care and Sleep Medicine the Dorothy M. Davis Heart and Lung Research Institute Ohio State University Columbus Ohio USA

Previously, we reported that M-CSF induced monocyte survival through the activation of Akt, p38MAPK and Erk1/2 kinases. Here, we found that Src family kinases were upstream of these kinases and played a central role in regulating M-CSF-induced monocyte survival. We observed that M-CSF promoted c-Src activation in monocytes and MDMs in a time-dependent manner. Src inhibitors reduced M-CSF-mediated phosphorylation of the M-CSF receptor (M-CSFR), Akt, Erk1/2, and p38 MAPK. We also observed that Src directly phosphorylated the M-CSFR. Notably, the inhibitors blocked phosphorylation of specific tyrosine residues within the M-CSFR. We further demonstrated that the Src inhibitor, PP2, attenuated M-CSF-induced NF-κB activation and M-CSF-induced monocyte survival. These findings indicated that Src family kinases mediate monocyte survival through the regulation of receptor phosphorylation and modulation of downstream signaling events. Thus, we predict that targeting Src family kinases may have therapeutic implication in inflammatory diseases.

关键词： Monocyte/Macrophage M-CSF Receptor Src Family kinases Cell Survival

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5'-Monophosphate-activated protein kinase (AMPK) improves autophagic activity in diabetes and diabetic complications

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Acta Pharmaceutica Sinica B 2016年第1期6卷 20-25页

作者： Fan Yao Ming Zhang Li Chen Department of Pharmacology College of Basic Medical SciencesJilin University School of Nursing Jilin University

Diabetes mellitus(DM),an endocrine disorder,will be one of the leading causes of death world-wide in about two decades.Cellular injuries and disorders of energy metabolism are two key factors in the pathogenesis of diabetes,which also become the important causes for the process of diabetic complications.AMPK is a key enzyme in maintaining metabolic homeostasis and has been implicated in the activation of autophagy in distinct tissues.An increasing number of researchers have confirmed that autophagy is a potential factor to affect or induce diabetes and its complications nowadays,which could remove cytotoxic proteins and dysfunctional organelles.This review will summarize the regulation of autophagy and AMPK in diabetes and its complications,and explore how AMPK stimulates autophagy in different diabetic syndromes.A deeper understanding of the regulation and activity of AMPK in autophagy would enhance its development as a promising therapeutic target for diabetes treatment.

关键词： Diabetes Autophagy AMP-activated protein kinases Diabetic complications

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Phosphorylation regulates cullin-based ubiquitination in tumorigenesis

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Acta Pharmaceutica Sinica B 2021年第2期11卷 309-321页

作者： Yifan Chen Xuejing Shao Ji Cao Hong Zhu Bo Yang Qiaojun He Meidan Ying Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China

Cullin-RING ligases(CRLs)recognize and interact with substrates for ubiquitination and degradation,and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes.Phosphorylation,either of substrates or receptors of CRLs,can alter their interaction.Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases,most often tumorigenesis.These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases,along with the regulation of the stability of specific oncoproteins and tumor suppressors.This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination,and most importantly its influence on tumorigenesis,to provide new directions and strategies for tumor therapy.

关键词： Phosphorylation Cullin-RING ligases Ubiquitination Tumorigenesis Targeted therapy Degradation Crosstalk kinases

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A LysM Receptor Heteromer Mediates Perception of Arbuscular Mycorrhizal Symbiotic Signal in Rice

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Molecular Plant 2019年第12期12卷 1561-1576页

作者： Jiangman He Chi Zhang Huiling Dai Huan Liu Xiaowei Zhang Jun Yang Xi Chen Yayun Zhu Dapeng Wang Xiaofeng Qi Weichao Li Zhihui Wang Guoyong An Nan YU Zuhua He Yong-Fei Wang Youli Xiao Peng Zhang Ertao Wang National Key Laboratory of Plant Molecular Genetics CAS Center for Excellence in Molecular Plant SciencesInstitute of Plant Physiology and EcologyShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai 200032China University of Chinese Academy of Sciences Beijing 100039China College of Life and Environment Sciences Shanghai Normal UniversityShanghai 200234China Collaborative Innovation Center of Crop Stress Biology Henan ProvinceInstitute of Plant Stress BiologyState Key Laboratory of Cotton BiologyDepartment of BiologyHenan UniversityKaifeng 475001China

Symbiotic microorganisms improve nutrient uptake by plants.To initiate mutualistic symbiosis with arbus-cular mycorrhizal(AM)fungi,plants perceive Myc factors,including lipochitooligosaccharides(LCOs)and short-chain chitooligosaccharides(CO4/CO5),secreted by AM fungi.However,the molecular mechanism of Myc factor perception remains elusive.In this study,we identified a heteromer of LysM receptor-like kinases consisting of OsMYR1/OsLYK2 and OsCERK1 that mediates the perception of AM fungi in rice.CO4 directly binds to OsMYR1,promoting the dimerization and phosphorylation of this receptor complex.Compared with control plants,Osmyr1 and Oscerk1 mutant rice plants are less sensitive to Myc factors and show decreased AM colonization.We engineered transgenic rice by expressing chimeric receptors that respectively replaced the ectodomains of OsMYR1 and OsCERK1 with those from the homologous Nod factor receptors MtNFP and MtL YK3 of Medicago truncatula.Transgenic plants displayed increased cal-cium oscillations in response to Nod factors compared with control rice.Our study provides significant mechanistic insights into AM symbiotic signal perception in rice.Expression of chimeric Nod/Myc recep-tors achieves a potentially important step toward generating cereals that host nitrogen-fixing bacteria.

关键词： rice arbuscular mycorrhizal symbiosis Myc factors Nod factors LysM receptor-like kinases

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TrkA regulates the regenerative capacity of bone marrow stromal stem cells in nerve grafts

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Neural Regeneration Research 2019年第10期14卷 1765-1771页

作者： Mei-Ge Zheng Wen-Yuan Sui Zhen-Dan He Yan Liu Yu-Lin Huang Shu-Hua Mu Xin-Zhong Xu Ji-Sen Zhang Jun-Le Qu Jian Zhang Dong Wang Department of Orthopedics The Seventh Hospital of Sun Yat-sen UniversityShenzhenGuangdong ProvinceChina Department of Orthopedics The Second Hospital of Anhui Medical UniversityHefeiAnhui ProvinceChina School of Medicine Shenzhen UniversityShenzhenGuangdong ProvinceChina Department of Scientific Research The Seventh Hospital of Sun Yat-sen UniversityShenzhenGuangdong ProvinceChina Psychology & Social College of Shenzhen University ShenzhenGuangdong ProvinceChina Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province College of Optoelectronic EngineeringShenzhen UniversityShenzhenGuangdong ProvinceChina

We previously demonstrated that overexpression of tropomyosin receptor kinase A(TrkA)promotes the survival and Schwann celllike differentiation of bone marrow stromal stem cells in nerve grafts,thereby enhancing the regeneration and functional recovery of the peripheral nerve.In the present study,we investigated the molecular mechanisms underlying the neuroprotective effects of TrkA in bone marrow stromal stem cells seeded into nerve grafts.Bone marrow stromal stem cells from Sprague-Dawley rats were infected with recombinant lentivirus vector expressing rat TrkA,TrkA-shRNA or the respective control.The cells were then seeded into allogeneic rat acellular nerve allografts for bridging a 1-cm right sciatic nerve defect.Then,8 weeks after surgery,hematoxylin and eosin staining showed that compared with the control groups,the cells and fibers in the TrkA overexpressing group were more densely and uniformly arranged,whereas they were relatively sparse and arranged in a disordered manner in the TrkA-shRNA group.Western blot assay showed that compared with the control groups,the TrkA overexpressing group had higher expression of the myelin marker,myelin basic protein and the axonal marker neurofilament 200.The TrkA overexpressing group also had higher levels of various signaling molecules,including TrkA,pTrkA(Tyr490),extracellular signal-regulated kinases 1/2(Erkl/2),pErk1/2(Thr202/Tyr204),and the anti-apoptotic proteins Bcl-2 and Bcl-xL.In contrast,these proteins were downregulated,while the pro-apoptotic factors Bax and Bad were upregulated,in the TrkA-shRNA group.The levels of the TrkA effectors Akt and pAkt(Ser473)were not different among the groups.These results suggest that TrkA enhances the survival and regenerative capacity of bone marrow stromal stem cells through upregulation of the Erk/Bcl-2 pathway.All procedures were approved by the Animal Ethical and Welfare Committee of Shenzhen University,China in December 2014(approval No.AEWC-2014-001219).

关键词： nerve regeneration bone marrow stromal stem cells tropomyosin receptor kinase A receptor lentiviral vector shRNA extracellular signal-regulated protein kinases 1/2 Bcl-2 nerve grafts peripheral nerve regeneration survival neural regeneration

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Shenfu injection attenuates lipopolysaccharide-induced myocardial inflammation and apoptosis in rats

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Chinese Journal of Natural Medicines 2020年第3期18卷 226-233页

作者： CHEN Rui-Juan RUI Qing-Lin WANG Qiong TIAN Fang WU Jian KONG Xiang-Qing Cardiology Department the First Affiliated Hospital with Nanjing Medical UniversityNanjing 210029China Emergency Department Affiliated Hospital of Nanjing University of Chinese MedicineJiangsu Province Hospital of Chinese MedicineNanjing 210029China Clinical Pharmacology Department Affiliated Hospital of Nanjing University of Chinese MedicineJiangsu Province Hospital of Chinese MedicineNanjing 210029China Central Laboratory Affiliated Hospital of Nanjing University of Chinese MedicineJiangsu Province Hospital of Chinese MedicineNanjing 210029China

Shenfu injection(SFI), a Chinese medicinal product, shows potent efficacy in treating sepsis. The aim of the present study was to clarify the protective effects of SFI against lipopolysaccharide(LPS)-induced myocardial inflammation and apoptosis.Experiments were carried out in Sprague-Dawley(SD) rats treated with LPS or LPS + SFI, and in H9 C2 cardiomyocytes. The sepsisassociated myocardial inflammation and apoptosis was induced by the intraperitoneal injection of LPS(20 mg·kg–1). SFI attenuated the increased expression of tumor necrosis factor(TNF)-α and interleukin(IL)-1β induced by LPS both in serum and heart. In LPS group,cell viability was reduced, and reversed after SFI administration. LPS treatment increased the expression levels of cleaved-caspase 3 and Bax, and those of Bcl2 and Bcl2/Bax. These two trends were reversed by SFI administration. The expression levels of phosphorylated mitogen-activated protein kinase kinase(p-MEK) and phosphorylated extracellular regulated protein kinases(p-ERK) were increased by LPS, and reversed by SFI. MEK inhibitor U0126 attenuated the apoptosis induced by LPS. These results indicate that SFI could treat LPS-induced cardiac dysfunction. In conclusion, SFI attenuates the inflammation and apoptosis induced by LPS via downregulating the MEK and ERK signaling pathways.

关键词： Shenfu injection Lipopolysaccharide Inflammation Apoptosis Mitogen-activated protein kinase kinase Extracellular regulated protein kinases

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p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation

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World Journal of Gastroenterology 2018年第33期24卷 3709-3723页

作者： Kai Wang Graham S Baldwin Mehrdad Nikfarjam Hong He Department of Surgery University of Melbourne

Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemotherapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases(PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemoresistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.

关键词： Pancreatic cancer Kras p21-activated kinases Cell signalling Chemo-resistance Immune response Tumour microenvironment

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