LIFE SCIENCES
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2025
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IF 5.1
Fangdi Wang,Li Hu,Xingyue Zeng,Wenbin You,Huijun Li,Bing Liu,Xiaohan Zhang
AKT is a pivotal kinase involved in diverse cellular processes, including tumorigenesis and glycogen metabolism. Ubiquitination modification of AKT has been reported as a critical cellular event that regulates its kinase activity and membrane translocation; however, the molecular mechanisms involved in AKT ubiquitination remain elusive. Here, we employed loss-of-function approaches and mutants of PDK1 with altered phosphorylation and modified nucleocytoplasmic shuttling behaviors to identify the functional roles of PDK1 on the ubiquitination of AKT. Our findings reveal that the nuclear entry of PDK1 in an importin7-dependent manner is required for insulin-induced TRAF6-mediated ubiquitination of AKT, which has been previously shown to occur in the nucleus. Moreover, the phosphorylation of PDK1 at S241 and the PI3K-mediated phosphorylation of PDK1 at S396 both regulate AKT ubiquitination by controlling nuclear entry of PDK1. These results provide new insights into the control of AKT signaling and suggest potential avenues for developing targeted AKT-modulating therapeutics.
研究领域:
分子生物学
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细胞信号传导
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生物化学
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内分泌学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
MEDICAL SCIENCE MONITOR
·
2019
·
IF 1.98
Guomin Li,Lirong Zeng,Haiyan Cheng,Jingxian Han,Xuezhu Zhang,Hui Xie
Background Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder. This study aimed to investigate effects of acupuncture administration on cognitive function and associated mechanisms. Material/Methods Senescence-accelerated prone 8 (SAM-P8) mice were randomly divided into 3 groups: the SAM-P8 group (P8-CN), the SAM-P8 administrating with acupuncture (P8-Acup) group, and the SAM-P8 administrating without acupuncture (P8-Sham) group. Morris water maze test was conducted to evaluate cognitive functions (memory and learning ability). PDK1, nPKC, and Rac1 inhibitors were used to treat SAM-P8 mice. Transmission electron microscope analysis was used to examine nuclear damage hippocampal tissues. Hematoxylin and eosin (H&E) staining was employed to evaluate inflammation. Western blot was used to detect PI3K, PDK1, nPKC, and Rac 1 expression in hippocampal tissues. Results Acupuncture administration significantly reduced PI3K, PDK1, nPKC, and Rac 1 levels compared to P8-CN group ( P <0.05). Both acupuncture and enzyme inhibitors (NSC23766, Rottlerin, {"type":"entrez-protein","attrs":{"text":"OSU03012","term_id":"1188654652","term_text":"OSU03012"}} OSU03012 ) significantly improved cognitive functions, reduced inflammation, and alleviated nuclear damages of SAM-P8 mice compared to P8-CN group ( P <0.05). Acupuncture significantly enhanced effects of inhibitors on inflammation and nuclear damages compared to inhibitor treatment single ( P <0.05). Acupuncture significantly enhanced down-regulative effects of {"type":"entrez-protein","attrs":{"text":"OSU03012","term_id":"1188654652","term_text":"OSU03012"}} OSU03012 on PI3K and PDK1 levels, increased down-regulative effects of Rottlerin on nPKC and Rac 1 levels and enhanced effects of Rottlerin on Rac 1 compared to P8-CN group ( P <0.05). Conclusions Acupuncture administration improved cognitive functions and alleviated inflammatory response and nuclear damage of SAM-P8 mice, by downregulating PI3K/PDK1/nPKC/Rac 1 signaling pathway. This study could provide potential insight for treating cognitive dysfunction and aging of AD patients.
研究领域:
神经生物学
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老年医学
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中医药学
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产品关联
DOI
PubMed
高影响因子
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
·
2022
·Vol. 48
·期 7
·e12839
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IF 6.25
Xiaolian Ye,Lu Chen,He Wang,Shixiao Peng,Mengjia Liu,Liyang Yao,Yizhi Zhang,Yun Stone Shi,Ying Cao,Jian-Jun Yang,Guiquan Chen
Aims Abundant recent evidence has shown that 3-phosphoinositide-dependent protein kinase 1 (PDK1) is activated in Alzheimer's disease (AD). However, it remains unknown whether inhibition of PDK1 in neurons may affect AD-like pathology in animal models of AD. Here, we aim to examine the effects of specific inactivation of neuronal PDK1 on pathology and behaviour in 5×FAD mice and to identify the underlying molecular mechanisms. Methods The Cre-loxP system was employed to generate Pdk1 cKO/5×FAD mice, in which PDK1 is inactivated in excitatory neurons in the adult forebrain. Cellular and behavioural techniques were used to examine plaque burden, inflammatory responses and spatial working memory in mice. Biochemical and molecular analyses were conducted to investigate relevant mechanisms. Results First, Aβ deposition was massively decreased and gliosis was highly attenuated in Pdk1 cKO/5×FAD mice compared with 5×FAD mice. Second, memory deficits were significantly improved in Pdk1 cKO/5×FAD mice. Third, APP levels were notably decreased in Pdk1 cKO/5×FAD mice. Fourth, mammalian target of rapamycin (mTOR) signalling and ribosome biogenesis were reduced in Pdk1 cKO/5×FAD mice. Conclusions Neuron-specific deletion of PDK1 robustly ameliorates AD-like pathology and improves spatial working memory in 5×FAD mice. We propose that genetic approach to inhibit PDK1 may be an effective strategy to slow AD.
研究领域:
神经科学
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分子生物学
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药理学
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遗传学
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产品关联
DOI
PubMed
高影响因子
ACS Pharmacology & Translational Science
·
2025
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IF 3.7
Yizhen Guo,Ding Huang,Yan Zhou,Maoxin Ran,Shaolin Zhang,Kin Yip Tam
Acquired resistance to osimertinib (OSI) poses a significant challenge in the treatment of epidermal growth factor receptor mutant non-small cell lung cancer (NSCLC). Although OSI is effective as a first-line salvage therapy in T790M-positive patients following progression on first- or second-generation EGFR-TKIs (erlotinib, gefitinib, and afatinib), the inevitable development of acquired resistance limits its therapeutic efficacy. This study reveals that OSI-resistant (OSIR) NSCLC cells underwent metabolic reprogramming characterized by enhanced glycolysis and upregulation of hexokinase 2 (HK2). We demonstrated that HK2 inhibitor, benserazide, exhibited significant anticancer effects in OSIR cell models and mediated by reactive oxygen species. Our results suggested that HK2 inhibition effectively modulated the enhanced glycolysis, activated the AMPK-mTOR-autophagy axis, and unexpectedly interfered with NF-κB signaling through direct HK2-IKKβ interaction. Excitingly, the protein expression level and activity of pyruvate dehydrogenase kinase 1 (PDK1) in OSIR cells were upregulated upon HK2 inhibition, indicating a pro-survival role. Combined inhibition of HK2 and PDK1 synergistically inhibited the proliferation of OSIR cells and significantly suppressed tumor growth in an OSIR cell xenograft model, outperforming the single use of HK2 inhibitor. This combination successfully rectified aberrant glucose metabolism and enhanced oxidative phosphorylation. Our findings identified HK2 as a crucial mediator in overcoming OSI resistance and suggested that combined inhibition of HK2 and PDK1 could be a promising approach in OSIR NSCLC.
研究领域:
肿瘤学
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分子生物学
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药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL ENDODONTIC JOURNAL
·
2026
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IF 6.4
Wenmin Wang,Jing Wang,Shuang Wu,Jie Wang,Zehan Li,Yadong Luo,Jintao Wu,Ming Yan,Na Li,Jinhua Yu
Aim Regenerative endodontics focuses on the restoration of the pulp-dentine complex by promoting odontogenic differentiation of stem cells of the apical papilla (SCAPs). Although SSUH2 has been implicated in developmental processes and dentine dysplasia type I (DD-I), the specific role of SSUH2 in regulating SCAPs differentiation remains unclear. In this study, we identified SSUH2 as a novel biomarker for SCAPs odontogenic differentiation and revealed its critical regulatory mechanism. Methodology Immunohistochemical staining of mouse mandibular first molar sections and immunofluorescence staining of human dental pulp tissues were performed to investigate the expression characteristics of SSUH2 during root development. SCAPs were treated with siRNA-mediated knockdown or lentivirus-mediated overexpression of SSUH2, followed by assessment of proliferation and odontogenic differentiation. Subcutaneous implantation of hydrogel-scaffold-root fragments loaded with SSUH2-overexpressing SCAPs in nude mice was performed to evaluate in vivo odontogenic capacity. Mechanistically, transcriptome sequencing and bioinformatic analysis identified downstream signalling pathways. Co-immunoprecipitation, nuclear-cytoplasmic fractionation, and immunofluorescence confirmed the direct interaction between SSUH2 and FOXM1, promoting FOXM1 nuclear translocation and subsequent transcriptional upregulation of PDK1. Moreover, transmission electron microscopy, mitochondrial membrane potential assays and ROS detection collectively demonstrated that SSUH2 regulates mitochondrial function in SCAPs via the FOXM1/PDK1 axis. Results During the development of the first molar in the mouse's lower jaw, SSUH2 is enriched in the root tip papilla region and it is also enriched in the root tip papilla region of humans. SSUH2 positively regulated the odontogenic differentiation of SCAPs in vitro. In vivo transplantation models showed that SSUH2 overexpression enhanced the odontogenic differentiation capacity of SCAPs and promoted dentine-pulp-like structure formation. Transcriptomic and functional analyses indicated that SSUH2 maintained mitochondrial function. SSUH2 directly interacted with FOXM1, promoted its nuclear translocation, and upregulated PDK1 expression. FOXM1 silencing abrogated SSUH2-mediated enhancement of both mitochondrial function and odontogenic differentiation in SCAPs. Conclusions Our study is the first to reveal that SSUH2 promotes the odontogenic differentiation of SCAPs through the FOXM1/PDK1 axis by regulating mitochondrial function. These findings suggest that SSUH2 could serve as a potential therapeutic target for enhancing the odontogenic differentiation of SCAPs and provide a novel strategic direction for pulp-dentine complex regeneration.
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
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IF 6.7
Hongyan Lin,Hongwei Han,Minkai Yang,Zhongling Wen,Qingqing Chen,Yudi Ma,Xuan Wang,Changyi Wang,Tongming Yin,Xiaoming Wang,Guihua Lu,Hongyuan Chen,Jinliang Qi,Yonghua Yang
Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only promote tumor growth and proliferation through accelerating aerobic glycolysis , but also contribute to drug resistance of non-small cell lung cancer (NSCLC). Considering that targeting PKM2 or PDK1 alone seems insufficient to remodel abnormal glucose metabolism to achieve significant antitumor activity , we proposed a “two-step approach” that regulates PKM2 and PDK1 synchronously. Firstly, we found that the combination of ML265 (PKM2 activator) and AZD7545 (PDK1 inhibitor) could synergistically inhibit proliferation and induce apoptosis in H1299 cells. Base on this, we designed a series of novel shikonin ( SK ) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 featuring a 2-methyl substitution on the benzene ring exerted significantly increased inhibitory activity toward EGFR mutant NSCLC cell H1975 (IC 50 = 1.51 μmol/L), which was 3 and 17-fold more active than the lead compound SK (IC 50 = 4.56 μmol/L) and the positive control gefitinib (IC 50 = 25.56 μmol/L), respectively. Additionally, E5 also showed good anti-tumor activity in xenografted mouse models, with significantly lower toxicity side effects than SK . Moreover, E5 also inhibited the entry of PKM2 into nucleus to regulate the transcriptional activation of oncogenes , thus restoring the sensitivity of H1975 cell to gefitinib. Collectively, these data demonstrate that E5 , a dual inhibitor of PKM2/PDK1, may be a promising adjunct to gefitinib in the treatment of EGFR-TKIs resistant NSCLC, deserving further investigation.
研究领域:
肿瘤学
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药理学
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癌症生物学
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代谢途径
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2023
·
IF 5.1
Yudi Ma,Xiaohui Lai,Zhongling Wen,Ziling Zhou,Minkai Yang,Qingqing Chen,Xuan Wang,Feng Mei,Liu Yang,Tongming Yin,Shucun Sun,Guihua Lu,Jinliang Qi,Hongyan Lin,Hongwei Han,Yonghua Yang
Warburg effect provides energy and material essential for tumor proliferation, the reverse of Warburg effect provides insights into the development of a novel anti-cancer strategy. Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only contribute to the Warburg effect through accelerating aerobic glycolysis, but also serve as druggable target for colorectal cancer (CRC). Considering that targeting PKM2 or PDK1 alone does not seem to be sufficient to remodel abnormal glucose metabolism and achieve significant antitumor activity, a series of novel benzenesulfonyl shikonin derivatives were designed to regulate PKM2 and PDK1 simultaneously. By means of molecular docking and antiproliferative screen, we found that compound Z10 could act as the combination of PKM2 activator and PDK1 inhibitor, thereby significantly inhibited glycolysis that reshaping tumor metabolism. Moreover, Z10 could inhibit proliferation, migration and induce apoptosis in CRC cell HCT-8. Finally, the in vivo anti-tumor activity of Z10 was evaluated in a colorectal cancer cell xenograft model in nude mice and the results demonstrated that Z10 induced tumor cell apoptosis and inhibited tumor cell proliferation with lower toxicity than shikonin. Our findings indicated that it is feasible to alter tumor energy metabolism through multi-target synergies, and the dual-target benzenesulfonyl shikonin derivative Z10 could be a potential anti-CRC agent.
研究领域:
药理学
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肿瘤学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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