BIOMATERIALS
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2015
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IF 8.557
Tingjie Yin,Lei Wang,Lifang Yin,Jianping Zhou,Meirong Huo
In this study, a novel redox-sensitive micellar system constructed from a hyaluronic acid-based amphiphilic conjugate (HA-ss-(OA-g-bPEI), HSOP) was successfully developed for tumor-targeted co-delivery of paclitaxel (PTX) and AURKA specific siRNA (si-AURKA). HSOP exhibited excellent loading capacities for both PTX and siRNA with adjustable dosing ratios and desirable redox-sensitivity independently verified by morphological changes of micelles alongside in vitro release of both drugs in different reducing environments. Moreover, flow cytometry and confocal microscopy analysis confirmed that HSOP micelles were capable of simultaneously delivering PTX and siRNA into MDA-MB-231 breast cancer cells via HA-receptor mediated endocytosis followed by rapid transport of cargoes into the cytosol. Successful delivery and transport amplified the synergistic effects between the drugs while leading to substantially greater antitumor efficacy when compared with single drug-loaded micelles and non-sensitive co-loaded micelles. In vivo investigation demonstrated that HSOP micelles could effectively accumulate in tumor sites and possessed the greatest antitumor efficacy over non-sensitive co-delivery control and redox-sensitive single-drug controls. These findings indicated that redox-sensitive HSOP co-delivery system holds great promise for combined drug/gene treatment for targeted cancer therapy.
研究领域:
药剂学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR MEDICINE
·
2023
·Vol. 29
·期 1
·1-21
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IF 5.7
Bai Tao,Li Mingxing,Liu Yuanfeng,Qiao Zhentao,Zhang Xusheng,Wang Yafeng,Wang Zhiwei
Background Diabetes-related limb ischemia is a challenge for lower extremity amputation. Aurora Kinase A (AURKA) is an essential serine/threonine kinase for mitosis, while its role in limb ischemia remains unclear. Method Human microvascular endothelial cells (HMEC-1) were cultured in high glucose (HG, 25 mmol/L d -glucose) and no additional growth factors (ND) medium to mimic diabetes and low growth factors deprivation as in vitro model. Diabetic C57BL/6 mice were induced by streptozotocin (STZ) administration. After seven days, ischemia was surgically performed by left unilateral femoral artery ligation on diabetic mice. The vector of adenovirus was utilized to overexpress AURKA in vitro and in vivo. Results In our study, HG and ND-mediated downregulation of AURKA impaired the cell cycle progression, proliferation, migration, and tube formation ability of HMEC-1, which were rescued by overexpressed AURKA. Increased expression of vascular endothelial growth factor A (VEGFA) induced by overexpressed AURKA were likely regulatory molecules that coordinate these events. Mice with AURKA overexpression exhibited improved angiogenesis in response to VEGF in Matrigel plug assay, with increased capillary density and hemoglobin content. In diabetic limb ischemia mice, AURKA overexpression rescued blood perfusion and motor deficits, accompanied by the recovery of gastrocnemius muscles observed by H&E staining and positive Desmin staining. Moreover, AURKA overexpression rescued diabetes-related impairment of angiogenesis, arteriogenesis, and functional recovery in the ischemic limb. Signal pathway results revealed that VEGFR2/PI3K/AKT pathway might be involved in AURKA triggered angiogenesis procedure. In addition, AURKA overexpression impeded oxidative stress and subsequent following lipid peroxidation both in vitro and in vivo, indicating another protective mechanism of AURKA function in diabetic limb ischemia. The changes in lipid peroxidation biomarkers (lipid ROS, GPX4, SLC7A11, ALOX5, and ASLC4) in in vitro and in vivo were suggestive of the possible involvement of ferroptosis and interaction between AUKRA and ferroptosis in diabetic limb ischemia, which need further investigation. Conclusions These results implicated a potent role of AURKA in diabetes-related impairment of ischemia-mediated angiogenesis and implied a potential therapeutic target for ischemic diseases of diabetes.
研究领域:
分子生物学
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细胞生物学
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糖尿病研究
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血管生物学
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产品关联
DOI
PubMed
高影响因子
UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS
·
2026
·Vol. 44
·期 11
·897-910
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IF 2.8
Guangye Han,Zhenhui Li,Weihang Song,Lei Li,Junling Hu
PTTG1 upregulation drives ENZ resistance via glycolysis. • AURKA phosphorylates PTTG1, causing nuclear translocation and Wnt/β-catenin. • Targeting AURKA/PTTG1 restores ENZ sensitivity in PCa xenografts. Background Prostate cancer (PCa), a common male malignant tumor, often develops resistance to the androgen receptor inhibitor enzalutamide (ENZ). Despite its established oncogenic role, pituitary tumor-transforming gene 1 (PTTG1)’s specific function and regulatory mechanism in ENZ-resistant PCa require investigation. Methods Cell biology assays were employed to evaluate the effects of PTTG1 and Aurora kinase A (AURKA) on cell proliferation, apoptosis, migration, and ENZ resistance. Bioinformatics analysis revealed that the glycolytic signaling pathway was significantly enriched in the PTTG1‑high expression group. Subsequently, the regulatory roles of PTTG1 and AURKA in glycolysis were verified by measuring glycolysis‑related metabolic parameters and changes in the expression of key proteins. The physical interaction between PTTG1 and AURKA was confirmed by predictions from protein–protein interaction databases and validated by co‑immunoprecipitation experiments. After determining the subcellular localization of PTTG1 through cell fractionation assays, we further assessed the effect of AURKA on the serine phosphorylation levels of the purified GFP–PTTG1 fusion protein. All in vitro results were validated in a nude mouse xenograft model using immunofluorescence, immunohistochemistry, and apoptosis detection assays. Results In ENZ-resistant PCa cells, PTTG1 was highly expressed, and its phosphorylation was promoted by AURKA, which in turn facilitated its nuclear translocation to activate Wnt signaling and glycolytic metabolism, driving ENZ resistance in PCa. Targeting the AURKA/PTTG1 axis enhanced ENZ sensitivity in a PCa mouse model. Conclusion The AURKA/PTTG1 axis contributes to ENZ resistance by promoting glycolytic metabolism in PCa cells.
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DOI
PubMed
高影响因子
BMC Systems Biology
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2018
·Vol. 12
·期 7
·11-17
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IF 2.05
Guo Mengjie,Lu Sicheng,Huang Hongming,Wang Yaohui,Yang Mary Q.,Yang Ye,Fan Zhimin,Jiang Bin,Deng Youping
Background Bladder cancer (BC) is the most common cancer of the urinary bladder and upper tract, in which the clinical management is limited. AURKA (aurora kinase A) has been identified as an oncogene in cancer development; however, its potential role and underlying mechanisms in the progression of BC remain unknown.Results In this study, we evaluated Aurora kinase A (AURKA) expression in patient samples by performing gene expression profiling, and found that AURKA expression levels were significantly higher in BC tissues than in normal tissues. Increased AURKA in BC was strongly associated with stage and grade. Moreover, BC patients with elevated AURKA achieved poor overall survival rates. The experiments in vitro comprehensively validated the critical role of AURKA in promoting BC cell proliferation using the methods of gene overexpression and gene silencing. Furthermore, we proved that AURKA inhibitor MLN8237 arrested BC cell growth and induced apoptosis.Conclusion sThese findings implicate AURKA acting as an effective biomarker for BC detection and prognosis, as well as therapeutic target.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
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