PHARMACOLOGICAL RESEARCH
·
2022
·
IF 10.334
Xiaona Xie,Xueding Cai,Feng Zhou,Yaozhe Li,Qianzi Liu,Luqiong Cai,Wenjing Zhu,Jinqiu Wei,Chenying Jin,Zitian Liu,Chunhui Jiang,Haiyang Zhao,Lehe Yang,Chengguang Zhao,Xiaoying Huang
Lung adenocarcinoma (LUAD) is associated with poor prognosis. Identifying novel cancer targets and helpful therapeutic strategies remains a serious clinical challenge. This study detected differentially expressed genes in The Cancer Genome Atlas (TCGA) LUAD data collection. We also identified a predictive DNA biomarker, G protein-coupled receptor 37 (GPR37), which was verified as a prognostic biomarker with a critical role in tumor progression. In human LUAD specimens and microarray analyses, we determined that GPR37 was significantly upregulated and associated with a poor prognosis. GPR37 downregulation markedly inhibited the proliferation and migration of LUAD both in vitro and in vivo . Mechanistically, GPR37 could bind to CDK6, thereby facilitating tumor progression in LUAD by inducing cell cycle arrest at the G1 phase. GPR37 also facilitates tumorigenesis in xenograft tumors in vivo . High-throughput screening for GPR37-targeted drugs was performed using the Natural Products Library, which revealed the potential of Hypocrellin B to inhibit GPR37 and cell growth in LUAD. We demonstrated that Hypocrellin B suppressed LUAD cell proliferation and migration both in vitro and in vivo via GPR37 inhibition. Collectively, our findings reveal the role of GPR37 in LUAD progression and migration and the potential of GPR37 as a target for the treatment of LUAD. Thus, the specific inhibition of GPR37 by the natural product Hypocrellin B may possess the potential for the treatment of LUAD.
研究领域:
肿瘤学
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分子生物学
·
药理学
·
癌症遗传学
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DOI
PubMed
高影响因子
Autophagy
·
2022
·
IF 13.391
Jie Yao,Shuming Tang,Chenyan Shi,Yunzhi Lin,Lanlan Ge,Qinghua Chen,Baoru Ou,Dongyu Liu,Yuyang Miao,Qiujie Xie,Xudong Tang,Jia Fei,Guangyi Yang,Jun Tian,Xiaobin Zeng
Isoginkgetin (ISO), a natural biflavonoid, exhibited cytotoxic activity against several types of cancer cells. However, its effects on hepatocellular carcinoma (HCC) cells and mechanism remain unclear. Here, we revealed that ISO effectively inhibited HCC cell proliferation and migration in vitro. LC3-II expression and autophagosomes were increased under ISO treatment. In addition, ISO-induced cell death was attenuated by treatment with chloroquine or knockdown of autophagy-related genes (ATG5 or ULK1). ISO significantly suppressed SLC2A1/GLUT1 (solute carrier family 2 member 1) expression and glucose uptake, leading to activation of the AMPK-ULK1 axis in HepG2 cells. Overexpression of SLC2A1/GLUT1 abrogated ISO-induced autophagy. Combining molecular docking with thermal shift analysis, we confirmed that ISO directly bound to the N terminus of CDK6 (cyclin-dependent kinase 6) and promoted its degradation. Overexpression of CDK6 abrogated ISO-induced inhibition of SLC2A1/GLUT1 transcription and induction of autophagy. Furthermore, ISO treatment significantly decreased the H3K27ac, H4K8ac and H3K4me1 levels on the SLC2A1/GLUT1 enhancer in HepG2 cells. Finally, ISO suppressed the hepatocarcinogenesis in the HepG2 xenograft mice and the diethylnitrosamine+carbon tetrachloride (DEN+CCl4)-induced primary HCC mice and we confirmed SLC2A1/GLUT1 and CDK6 as promising oncogenes in HCC by analysis of TCGA data and human HCC tissues. Our results provide a new molecular mechanism by which ISO treatment or CDK6 deletion promotes autophagy; that is, ISO targeting the N terminus of CDK6 for degradation inhibits the expression of SLC2A1/GLUT1 by decreasing the enhancer activity of SLC2A1/GLUT1, resulting in decreased glucose levels and inducing the AMPK-ULK1 pathway.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Long Zheng,Yiwei Zheng,Sijie Wu,Yonglei Zhang,Zhongwen Luo,Yuhan Jiang,Shunxin Guo,Meiting Zou,Lingyi Kong,Xiaobing Wang
The clinical application of CDK4/6 inhibitors is constrained by their narrow indications. To improve therapeutic efficacy against breast cancer, combination therapies using CDK4/6 inhibitors with BET inhibitors are being explored in clinical trials. Our study demonstrates that the CDK4/6 inhibitor Abemaciclib and the BRD4 inhibitor BQ0 exert a synergistic effect in inhibiting the proliferation of triple-negative breast cancer (TNBC) cells in vitro. Based on these findings, we designed and synthesized a series of dual-target inhibitors that simultaneously target CDK6 and BRD4. Among the newly synthesized compounds, 7f and 7f15 exhibited potent inhibitory activity against both CDK6 and BRD4, along with remarkable antiproliferative activity on TNBC cells. In vivo studies using the MDA-MB-231 xenograft mouse model revealed that 7f15 exhibits robust antitumor activity without significant adverse effects. The kinases selectivity experimental suggested that 7f15 is a pan-BET inhibitor. In summary, 7f15, hereby designated as KWZL-7f15, is a novel dual CDK6/BET inhibitor with promising therapeutic potential for the treatment of triple-negative breast cancer.
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Yonglei Zhang,Fucheng Yin,Zhongwen Luo,Yiwei Zheng,Shunxin Guo,Sijie Wu,Yuhan Jiang,Long Zheng,Liangliang Ma,Meiting Zou,Xiaobing Wang,Lingyi Kong
Poly(ADP-ribose) polymerase (PARP) inhibitors have been approved and marketed for the treatment of BRCA-mutated breast and ovarian cancers. Recent studies have demonstrated that cyclin-dependent kinase 4/6 (CDK4/6) inhibitors can induce defects in homologous recombination (HR) repair, thereby sensitizing breast cancer cells with HR proficiency to PARP inhibitors through a synthetic lethal mechanism. Here, we report the rational design and synthesis of a potent dual PARP/CDK6 inhibitor 11, which was identified through SAR studies. Compound 11 effectively induces excessive DNA damage and apoptosis in MDA-MB-231 cells, while maintaining robust inhibitory activity against both PARP and CDK6. Additionally, 11 demonstrates excellent antitumor efficacy and antimetastatic properties, with no evident toxicity or side effects observed. Further investigations revealed that 11 could inhibit tumor cell proliferation by modulating the Wnt/β-catenin signaling pathway. In summary, these findings highlight the potential therapeutic advantages of 11, coded with KWZY-11, in treating BRCA wild-type tumors.
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2018
·Vol. 42
·期 1
·61-70
·
IF 2.784
Yuhuan Ma,Wenwei Zheng,Houhuang Chen,Xiang Shao,Pingdong Lin,Xianxiang Liu,Xihai Li,Hongzhi Ye
The present study investigated the mechanism underlying the effects of glucosamine (GlcN) on the proliferation of chondrocytes isolated from the knee cartilage of Sprague‑Dawley rats. Chondrocytes were treated with various concentrations of GlcN or without GlcN. The effects of GlcN on chondrocyte proliferation were determined using reverse transcription‑polymerase chain reaction, western blot analysis and immunohistochemistry. The results indicated that GlcN significantly improved chondrocyte viability, accelerated G1/S transition during progression of the cell cycle and promoted the expression of cell cycle regulatory proteins, including cyclin D1, cyclin‑dependent kinase (CDK)4 and CDK6, thus indicating that GlcN may promote chondrocyte proliferation. Furthermore, GlcN upregulated the expression levels of Wnt‑4, Frizzled‑2 and β‑catenin, and downregulated the expression of glycogen synthase kinase‑3. GlcN also promoted β‑catenin translocation; β‑catenin is able to activate numerous downstream target genes, including cyclin D1. To determine the role of the Wnt/β‑catenin signaling pathway in chondrocyte proliferation, the Wnt/β‑catenin signaling pathway was inhibited using Dickkopf‑1 (DKK‑1), after which chondrocytes were treated with GlcN. The results demonstrated that the expression levels of β‑catenin and cyclin D1 were decreased in chondrocytes treated with DKK‑1 and GlcN. These results suggested that GlcN may promote chondrocyte proliferation via the Wnt/β‑catenin signaling pathway.
研究领域:
药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
LABORATORY INVESTIGATION
·
2022
·Vol. 102
·期 5
·494-504
·
IF 5.502
Tao Lianyuan,Li Deyu,Mu Sengmao,Tian Guanjing,Yan Guoyi
We explored the biological role of long non-coding RNA (lncRNA) MAPKAPK5_AS1 (MAAS) and the mechanism of its differential expression in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Differentially expressed lncRNAs in HBV-related HCC were determined using bioinformatics analysis. Gain-of-function experiments were conducted to evaluate the effect of MAAS on cell proliferation. A xenograft model was established for in vivo experiments. Dual-luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation, and methylated RNA immunoprecipitation were performed to elucidate the underlying molecular mechanisms. MAAS was upregulated in HBV-related HCC cancerous tissues and its high expression was closely related to the poor survival probability of patients. Functional assays revealed that MAAS overexpression facilitated the proliferation of HBV + HCC cells in vitro and in vivo. Mechanistically, MAAS promoted the MYC proto-oncogene (c-Myc)-induced transcriptional activation of cyclin-dependent kinase 4 (CDK4), CDK6, and S-phase kinase associated protein 2 via stabilizing c-Myc protein, thereby facilitating G1/S transition. The latter contributed to the paradoxical proliferation of HBV + HCC cells. Although MAAS was upregulated in HBV-related HCC cancerous tissues, it was highly expressed in M2 macrophages, a major phenotype of tumor-associated macrophages in HBV-related HCC, instead of in HBV + HCC cells. HBeAg, an HBV-associated antigen, further elevated the MAAS level in M2 macrophages by enhancing the methyltransferase-like 3-mediated N6-methyladenosine modification of MAAS. The increased MAAS in the M2 macrophages was then transferred to HBV + HCC cells through the M2 macrophage-derived exosomes, promoting cell proliferation. Our findings show that HBV + HCC cell-secreted HBeAg upregulates MAAS expression in M2 macrophages by affecting its m 6 A modification. The upregulated MAAS is then transferred to HBV + HCC cells via exosomes, facilitating the proliferation of HBV + HCC cells by targeting c-Myc.
研究领域:
分子生物学
·
肿瘤学
·
病毒学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2023
·
IF 8.8
Zhen-Ning Zhang,Dan-Lei Yang,Hai Liu,Jue Bi,Ya-Bo Bao,Jiao-Yang Ma,Qin-Xiang Zheng,Dao-Lei Cui,Wei Chen,Ping Xiang
Tris(2-chloroisopropyl) phosphate (TCPP) and Tris(2-chloroethyl) phosphate (TCEP) are the widely used organophosphorus flame retardants indoors and easily accessible to the eyes as the common adhesive components of dust and particle matter, however, hardly any evidence has demonstrated their corneal toxicity. In this study, the adverse effects of TCPP, TCEP, and TCPP + TCEP exposure on human corneal epithelial cells (HCECs) were investigated. The cell viability and morphology, intracellular reactive oxygen species (ROS), cell cycle, and the expressions of cell cycle and pyroptosis-related genes were assessed to explain the underlying mechanisms. Compared to individual exposure, co-exposure to TCPP 20 +TCEP 20 showed higher cytotoxicity with a sharp decrease of >30% in viability and more serious oxidative damage by increasing ROS production to 110.92% compared to the control group. Furthermore, the cell cycle arrested at the S phase (36.20%) was observed after combined treatment, evidenced by the upregulation of cyclin D1 , CDK2 , CDK4 , CDK6 , p21, and p27 . Interestingly, pyroptosis-related genes GSDMD , Caspase-1 , NLRP3 , IL-1β , IL-18 , NLRP1, and NLRC4 expressions were promoted with cell swelling and glowing morphology. Oxidative stress and cell cycle arrest probably acted as a key role in TCPP 20 +TCEP 20 -induced cytotoxicity and pyroptosis in HCECs. Our results suggested that TCPP 20 +TCEP 20 co-exposure induced severer corneal damage, further illustrating its significance in estimating indoor health hazards to humans.
研究领域:
毒理学
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细胞生物学
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眼科学
·
环境健康
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产品关联
DOI
PubMed
高影响因子
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