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

《医学前沿（英文）》 2023年 第17卷 第4期   页码 714-728 doi: 10.1007/s11684-022-0959-5

摘要： 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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Prohibitin regulates mTOR pathway via interaction with FKBP8

Jiahui Zhang, Yanan Yin, Jiahui Wang, Jingjing Zhang, Hua Liu, Weiwei Feng, Wen Yang, Bruce Zetter, Yingjie Xu

《医学前沿（英文）》 2021年 第15卷 第3期   页码 448-459 doi: 10.1007/s11684-020-0805-6

摘要： The ability of tumor cells to sustain continuous proliferation is one of the major characteristics of cancer. The activation of oncogenes and the mutation or inactivation of tumor suppressor genes ensure the rapid proliferation of tumor cells. The PI3K–Akt–mTOR axis is one of the most frequently modified signaling pathways whose activation sustains cancer growth. Unsurprisingly, it is also one of the most commonly attempted targets for cancer therapy. FK506 binding protein 8 (FKBP8) is an intrinsic inhibitor of mTOR kinase that also exerts an anti-apoptotic function. We aimed to explain these contradictory aspects of FKBP8 in cancer by identifying a “switch” type regulator. We identified through immunoprecipitation–mass spectrometry-based proteomic analysis that the mitochondrial protein prohibitin 1 (PHB1) specifically interacts with FKBP8. Furthermore, the downregulation of PHB1 inhibited the proliferation of ovarian cancer cells and the mTOR signaling pathway, whereas the FKBP8 level in the mitochondria was substantially reduced. Moreover, concomitant with these changes, the interaction between FKBP8 and mTOR substantially increased in the absence of PHB1. Collectively, our finding highlights PHB1 as a potential regulator of FKBP8 because of its subcellular localization and mTOR regulating role.

关键词： prohibitin 1     FKBP8     mTOR     cell proliferation     cancer    

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mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

Shi-Yong Sun

《医学前沿（英文）》 2021年 第15卷 第2期   页码 221-231 doi: 10.1007/s11684-020-0812-7

摘要： The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.

关键词： mTOR     cancer therapy     resistance     GSK3     protein degradation     E3 ubiquitin ligase     PD-L1    

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Resveratrol reduces intracellular reactive oxygen species levels by inducing autophagy through the AMPK-mTORpathway

Jun Song, Yeping Huang, Wenjian Zheng, Jing Yan, Min Cheng, Ruxing Zhao, Li Chen, Cheng Hu, Weiping Jia

《医学前沿（英文）》 2018年 第12卷 第6期   页码 697-706 doi: 10.1007/s11684-018-0655-7

摘要：

Oxidative stress induced by free fatty acid aggravates endothelial injury, which leads to diabetic cardiovascular complications. Reduction of intracellular oxidative stress may attenuate these pathogenic processes. The dietary polyphenol resveratrol reportedly exerts potential protective effects against endothelial injury. This study determined whether resveratrol can reduce the palmitic acid (PA)-induced generation of reactive oxygen species (ROS) and further explored the underlying molecular mechanisms. We found that resveratrol significantly reduced the PA-induced endothelial ROS levels in human aortic endothelial cells. Resveratrol also induced endothelial cell autophagy, which mediated the effect of resveratrol on ROS reduction. Resveratrol stimulated autophagy via the AMP-activated protein kinase (AMPK)-mTOR pathway. Taken together, these data suggest that resveratrol prevents PA-induced intracellular ROS by autophagy regulation via the AMPK-mTOR pathway. Thus, the induction of autophagy by resveratrol may provide a novel therapeutic candidate for cardioprotection in metabolic syndrome.

关键词： resveratrol     reactive oxygen species     AMPK     mTOR     autophagy    

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Low-temperature caproate production, microbial diversity, and metabolic pathway in xylose anaerobic fermentation

《环境科学与工程前沿（英文）》 2023年 第17卷 第3期 doi: 10.1007/s11783-023-1637-9

摘要：

● Converting xylose to caproate under a low temperature of 20 °C by MCF was verified.

关键词： Xylose fermentation     Caproate     Low temperature     Bifidobacterium     FAB pathway     RBO pathway    

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低蛋白日粮中添加亮氨酸通过雷帕霉素靶蛋白信号通路增加成年大鼠骨骼肌重量及蛋白质合成

张博, 楚丽翠, 刘宏, 谢春元, 谯仕彦, 曾祥芳

《工程（英文）》 2017年 第3卷 第5期   页码 760-765 doi: 10.1016/J.ENG.2017.03.008

摘要： 试验第11天，所有大鼠大剂量一次性腹腔注射L-[ring-2H5]苯丙氨酸注射液，测定血清中的氨基酸含量、比目鱼肌和腓肠肌重量、蛋白质合成速率及mTOR信号通路相关分子的表达。本文结论如下，在成年大鼠长期采食低蛋白日粮的情况下，日粮中添加亮氨酸可以改善大鼠的生长性能，通过提高mTOR通路中S6K1磷酸化水平，促进大鼠骨骼肌蛋白质合成，抑制蛋白质降解。

关键词： 低蛋白日粮     亮氨酸     生长性能     肌肉重量     蛋白质合成     成年大鼠    

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Exploring the methodology and application of clinical pathway in evidence-based Chinese medicine

Sicheng Wang, He Yu, Jianping Liu, Baoyan Liu

《医学前沿（英文）》 2011年 第5卷 第2期   页码 157-162 doi: 10.1007/s11684-011-0128-8

摘要： At present, clinical pathway has become one of the most important health care reform measures in many countries. In this study, the authors introduced basic concepts and explored the application of the clinical pathway of evidence-based Chinese medicine incorporated with the methodology from the concepts of management, evidence-based medicine, operational research and health economics. Such concepts provide examples and experiences, on which the application of clinical pathway in Chinese medicine practice in China can be based.

关键词： evidence-based medicine     clinical pathway     methodology     concept     technical difficulty    

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Endogenous tissue factor pathway inhibitor in vascular smooth muscle cells inhibits arterial thrombosis

null

《医学前沿（英文）》 2017年 第11卷 第3期   页码 403-409 doi: 10.1007/s11684-017-0522-y

摘要：

Tissue factor pathway inhibitor (TFPI) is the main inhibitor of tissue factor-mediated coagulation. TFPI is expressed by endothelial and smooth muscle cells in the vasculature. Endothelium-derived TFPI has been reported to play a regulatory role in arterial thrombosis. However, the role of endogenous TFPI in vascular smooth muscle cells (VSMCs) in thrombosis and vascular disease development has yet to be elucidated. In this TFPIFlox mice crossbred with Sma–Cre mice were utilized to establish TFPI conditional knockout mice and to examine the effects of VSMC-directed TFPI deletion on development, hemostasis, and thrombosis. The mice with deleted TFPI in VSMCs (TFPISma) reproduced viable offspring. Plasma TFPI concentration was reduced 7.2% in the TFPISma mice compared with TFPIFlox littermate controls. Plasma TFPI concentration was also detected in the TFPITie2 (mice deleted TFPI in endothelial cells and cells of hematopoietic origin) mice. Plasma TFPI concentration of the TFPITie2 mice was 80.4% lower (P<0.001) than that of the TFPIFlox mice. No difference in hemostatic measures (PT, APTT, and tail bleeding) was observed between TFPISma and TFPIFlox mice. However, TFPISma mice had increased ferric chloride–induced arterial thrombosis compared with TFPIFlox littermate controls. Taken together, these data indicated that endogenous TFPI from VSMCs inhibited ferric chloride–induced arterial thrombosis without causing hemostatic effects.

关键词： arterial thrombosis     conditional knockout mice     tissue factor pathway inhibitor     vascular smooth muscle cells    

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Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair

《医学前沿（英文）》 2022年 第16卷 第4期   页码 637-650 doi: 10.1007/s11684-021-0864-3

摘要： Oxidative stress plays an important role in the pathogenesis of aminoglycoside-induced hearing loss and represents a promising target for treatment. We tested the potential effect of apigenin, a natural flavonoid with anticancer, anti-inflammatory, and antioxidant activities, on neomycin-induced ototoxicity in cochlear hair cells in vitro. Results showed that apigenin significantly ameliorated the loss of hair cells and the accumulation of reactive oxygen species upon neomycin injury. Further evidence suggested that the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was activated by apigenin treatment. Disruption of the Nrf2 axis abolished the effects of apigenin on the alleviation of oxidative stress and subsequent apoptosis of hair cells. This study provided evidence of the protective effect of apigenin on cochlear hair cells and its underlying mechanism.

关键词： apigenin     aminoglycosides     ototoxicity     oxidative stress     Nrf2 signaling pathway    

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Biosynthetic pathway of terpenoid indole alkaloids in Catharanthus roseus

null

《医学前沿（英文）》 2014年 第8卷 第3期   页码 285-293 doi: 10.1007/s11684-014-0350-2

摘要：

Catharanthus roseus is one of the most extensively investigated medicinal plants, which can produce more than 130 alkaloids, including the powerful antitumor drugs vinblastine and vincristine. Here we review the recent advances in the biosynthetic pathway of terpenoid indole alkaloids (TIAs) in C. roseus, and the identification and characterization of the corresponding enzymes involved in this pathway. Strictosidine is the central intermediate in the biosynthesis of different TIAs, which is formed by the condensation of secologanin and tryptamine. Secologanin is derived from terpenoid (isoprenoid) biosynthetic pathway, while tryptamine is derived from indole biosynthetic pathway. Then various specific end products are produced by different routes during downstream process. Although many genes and corresponding enzymes have been characterized in this pathway, our knowledge on the whole TIA biosynthetic pathway still remains largely unknown up to date. Full elucidation of TIA biosynthetic pathway is an important prerequisite to understand the regulation of the TIA biosynthesis in the medicinal plant and to produce valuable TIAs by synthetic biological technology.

关键词： Catharanthus roseus     terpenoidindole alkaloids     biosynthetic pathway     vinblastine     vincristine    

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Autophagy and the nutritional signaling pathway

Long HE,Shabnam ESLAMFAM,Xi MA,Defa LI

《农业科学与工程前沿（英文）》 2016年 第3卷 第3期   页码 222-230 doi: 10.15302/J-FASE-2016106

摘要： During their growth and development, animals adapt to tremendous changes in order to survive. These include responses to both environmental and physiological changes and autophagy is one of most important adaptive and regulatory mechanisms. Autophagy is defined as an autolytic process to clear damaged cellular organelles and recycle the nutrients via lysosomic degradation. The process of autophagy responds to special conditions such as nutrient withdrawal. Once autophagy is induced, phagophores form and then elongate and curve to form autophagosomes. Autophagosomes then engulf cargo, fuse with endosomes, and finally fuse with lysosomes for maturation. During the initiation process, the ATG1/ULK1 (unc-51-like kinase 1) and VPS34 (which encodes a class III phosphatidylinositol (PtdIns) 3-kinase) complexes are critical in recruitment and assembly of other complexes required for autophagy. The process of autophagy is regulated by autophagy related genes (ATGs). Amino acid and energy starvation mediate autophagy by activating mTORC1 (mammalian target of rapamycin) and AMP-activated protein kinase (AMPK). AMPK is the energy status sensor, the core nutrient signaling component and the metabolic kinase of cells. This review mainly focuses on the mechanism of autophagy regulated by nutrient signaling especially for the two important complexes, ULK1 and VPS34.

关键词： Autophagy     ULK1 complex     VPS34 complex     AMPK     mTOR     nutrient signaling    

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Genetic evidence in planar cell polarity signaling pathway in human neural tube defects

null

《医学前沿（英文）》 2014年 第8卷 第1期   页码 68-78 doi: 10.1007/s11684-014-0308-4

摘要：

Neural tube defects (NTDs) are a group of birth anomalies having a profound physical, emotional, and financial effects on families and communities. Their etiology is complex, involving environmental and genetic factors that interact to modulate the incidence and severity of the developing phenotype. The planar cell polarity (PCP) pathway controls the process of convergent extension (CE) during gastrulation and neural tube closure and has been implicated in the pathogenesis of NTDs in animal models and human cohorts. This review summarizes the cumulative results of recent studies on PCP signaling pathway and human NTDs. These results demonstrate that PCP gene alterations contribute to the etiology of human NTDs.

关键词： planar cell polarity     neural tube defects     rare mutations    

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NETO2 promotes melanoma progression via activation of the Ca/CaMKII signaling pathway

《医学前沿（英文）》 2023年 第17卷 第2期   页码 263-274 doi: 10.1007/s11684-022-0935-0

摘要： Melanoma is the most aggressive cutaneous tumor. Neuropilin and tolloid-like 2 (NETO2) is closely related to tumorigenesis. However, the functional significance of NETO2 in melanoma progression remains unclear. Herein, we found that NETO2 expression was augmented in melanoma clinical tissues and associated with poor prognosis in melanoma patients. Disrupting NETO2 expression markedly inhibited melanoma proliferation, malignant growth, migration, and invasion by downregulating the levels of calcium ions (Ca2+) and the expression of key genes involved in the calcium signaling pathway. By contrast, NETO2 overexpression had the opposite effects. Importantly, pharmacological inhibition of CaMKII/CREB activity with the CaMKII inhibitor KN93 suppressed NETO2-induced proliferation and melanoma metastasis. Overall, this study uncovered the crucial role of NETO2-mediated regulation in melanoma progression, indicating that targeting NETO2 may effectively improve melanoma treatment.

关键词： melanoma     neuropilin and tolloid-like 2     Ca2+/CaMKII signaling pathway    

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Xiao Ke Qing improves glycometabolism and ameliorates insulin resistance by regulating the PI3K/Akt pathway

Xiaoqing Li, Xinxin Li, Genbei Wang, Yan Xu, Yuanyuan Wang, Ruijia Hao, Xiaohui Ma

《医学前沿（英文）》 2018年 第12卷 第6期   页码 688-696 doi: 10.1007/s11684-018-0662-8

摘要：

Xiao Ke Qing (XKQ) granule has been clinically used to treat type 2 diabetes mellitus (T2DM) for 10 years in Chinese traditional medication. However, its mechanisms against hyperglycemia remain poorly understood. This study aims to investigate XKQ mechanisms on diabetes and diabetic liver disease by using the KKAy mice model. Our results indicate that XKQ can significantly reduce food and water intake. XKQ treatment also remarkably decreases both the fasting blood glucose and blood glucose in the oral glucose tolerance test. Additionally, XKQ can significantly decrease the serum alanine aminotransferase level and liver index and can alleviate the fat degeneration in liver tissues. Moreover, XKQ can ameliorate insulin resistance and upregulate the expression of IRS-1, PI3K (p85), p-Akt, and GLUT4 in the skeletal muscle of KKAy mice. XKQ is an effective drug for T2DM by ameliorating insulin resistance and regulating the PI3K/Akt signaling pathway in the skeletal muscle.

关键词： XKQ     type 2 diabetes mellitus     KKAy mice     PI3K/Akt pathway     diabetic liver disease    

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Wnt/β-catenin signaling pathway and its role in hepatocellular carcinoma

ZHANG Xufeng, YU Liang, LU Yi

《医学前沿（英文）》 2008年 第2卷 第3期   页码 216-228 doi: 10.1007/s11684-008-0042-x

摘要： Wnt/?-catenin signaling pathway has been identified as a key cellular pathway in embryogenesis and disease, including cancers. In recent years, more and more interacting components have been observed and their exact functions approached, thus ensuring the most complicated understanding of this pathway in normal organism development and disorders. In hepatocellular carcinoma (HCC), with a deeply understanding of this pathway, more and more genes which contribute to aberrant activation of Wnt/?-catenin signaling pathway has recently been identified and their exact roles in HCC pursued. In this review, we will focus on a mostly updated understanding of this pathway and its observed role in HCC by emphasizing the gene defects identified to promote tumorigenesis and development.

关键词： interacting     complicated understanding     embryogenesis     activation     organism development    

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标题 作者 时间 类型 操作

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

期刊论文

Prohibitin regulates mTOR pathway via interaction with FKBP8

Jiahui Zhang, Yanan Yin, Jiahui Wang, Jingjing Zhang, Hua Liu, Weiwei Feng, Wen Yang, Bruce Zetter, Yingjie Xu

期刊论文

mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

Shi-Yong Sun

期刊论文

Resveratrol reduces intracellular reactive oxygen species levels by inducing autophagy through the AMPK-mTORpathway

Jun Song, Yeping Huang, Wenjian Zheng, Jing Yan, Min Cheng, Ruxing Zhao, Li Chen, Cheng Hu, Weiping Jia

期刊论文

Low-temperature caproate production, microbial diversity, and metabolic pathway in xylose anaerobic fermentation

期刊论文

低蛋白日粮中添加亮氨酸通过雷帕霉素靶蛋白信号通路增加成年大鼠骨骼肌重量及蛋白质合成

张博, 楚丽翠, 刘宏, 谢春元, 谯仕彦, 曾祥芳

期刊论文

Exploring the methodology and application of clinical pathway in evidence-based Chinese medicine

Sicheng Wang, He Yu, Jianping Liu, Baoyan Liu

期刊论文

Endogenous tissue factor pathway inhibitor in vascular smooth muscle cells inhibits arterial thrombosis

null

期刊论文

Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair

期刊论文

Biosynthetic pathway of terpenoid indole alkaloids in Catharanthus roseus

null

期刊论文

Autophagy and the nutritional signaling pathway

Long HE,Shabnam ESLAMFAM,Xi MA,Defa LI

期刊论文

Genetic evidence in planar cell polarity signaling pathway in human neural tube defects

null

期刊论文

NETO2 promotes melanoma progression via activation of the Ca/CaMKII signaling pathway

期刊论文

Xiao Ke Qing improves glycometabolism and ameliorates insulin resistance by regulating the PI3K/Akt pathway

Xiaoqing Li, Xinxin Li, Genbei Wang, Yan Xu, Yuanyuan Wang, Ruijia Hao, Xiaohui Ma

期刊论文

Wnt/β-catenin signaling pathway and its role in hepatocellular carcinoma

ZHANG Xufeng, YU Liang, LU Yi

期刊论文