Frontiers in Pharmacology
·
2019
·
IF 3.845
Peng Mei,Deng Jun,Zhou Sichun,Xiao Di,Long Jiahui,Zhang Nan,He Caimei,Mo Miao,Yang Xiaoping
Activations of Akt or ERK pathway induced by clinical drugs promote therapeutic failure due to decrease of drug response, and no available strategies have been developed to solve these problems. In this study, we found that pirarubicin (THP), one important chemotherapeutic drug for treating bladder cancer intravesically, dramatically elevated phosphorylations of both Akt and Erk1/2 in addition to inducing DNA damage. MK2206 or AZD6244, representative Akt and Erk1/2 inhibitors, respectively, profoundly sensitized bladder cancer cells to THP treatment. Interestingly, we found that inhibition of a single arm of either Akt or Erk1/2 pathway would induce the increase of another arm, indicating the existence of the crosstalk between these two pathways. Thus, simultaneous suppression of both signals may be needed for increasing the sensitivity of THP. On the other hand, we revealed that phenformin efficiently inhibited both Akt and Erk1/2 phosphorylation in a dose-dependent manner. Furthermore, we demonstrated that phenformin, mimicking dual inhibitors, plays dramatically synergistic action with THP both in vitro and in vivo. Our findings suggest that combination therapy of THP with dual inhibitors may constitute a successful strategy for improving chemotherapy response.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Cancer Genetics
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2023
·
IF 1.9
Shuoyi Zhang,Ming Zhong,Hongbo Zhu,Qinghua You,Hao Yuan,Yongping Li
ABSTRACT We investigated the effect of stem cell marker dopamine receptor D2 (DRD2) on the proliferation of hormone-receptor-negative breast cancer cells. High-throughput DNA methylation sequencing on an 850K chip was used to pre-screen breast cancer tissues with significant methylation differences. The expression of DRD2 in breast cancer and normal breast tissues, and clinical risk factors, were detected by pyrophosphoric acid validation and immunohistochemistry. In vitro and in vivo experiments verified the possible molecular signaling pathways. DRD2 promoter region was hypomethylated in hormone-receptor-negative breast cancer or with high-risk factors compared to the normal tissues. The proliferation of breast cancer cells was enhanced after DRD2 was upregulated and decreased after DRD2 was downregulated. In vivo experiments found that tumor growth and the expression of antigen KI-67 (Ki67) and the cluster of differentiation 31 (CD31) were improved by the overexpression of DRD2 and inhibited by the down expression of DRD2. In vivo and in vitro experiments demonstrated the phosphorylation of filamin A and extracellular signal-regulated kinase (FLNA-ERK) was influenced by the expression of DRD2, suggesting DRD2 plays a role in the FLNA-ERK signaling pathway. Methylation inhibitors (5-aza-2-deoxycytidine, 5-azadc) partially reversed the inhibitory effect of DRD2 down expression on cell proliferation, migration, and tumor growth in animal models, indicating that inhibition of DRD2 methylation promotes cancer development. This study demonstrated the DRD2 promoter region is hypomethylated in hormone-receptor-negative breast cancer or with high-risk factors. The methylation status of the DRD2 promoter and FLNA-ERK signaling pathway and the DRD2 expression in breast cancer treatment need to be considered.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
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DOI
PubMed
高影响因子
Cancer Management and Research
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2020
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IF 2.886
Yanshi Wang,Shaojie Yang,Shanshan Zhang,Xin Wu
Purpose To evaluate the anti-tumor effects of oxymatrine in vulvar squamous cell carcinoma (VSCC) cells and to explore the underlying mechanisms. Methods We selected SW962 and A431 VSCC cell lines. Cell proliferation was examined using MTT assay. Cell cycle and apoptosis were detected using flow cytometry. Migration and invasion were evaluated using transwell and wound-healing assays. The relevant protein expression and signaling pathways were analyzed using Western blotting. Results Oxymatrine inhibited the proliferation of SW962 and A431 VSCC cells in a time- and dose-dependent manner. Oxymatrine induced cell cycle arrest in the G2/M phase by increasing the protein expression of P21 and decreasing levels of cyclin B1 and CDC2. Oxymatrine upregulated the expression of cleaved-caspase 3 and BAX and downregulated the expression of BCL2, which led to an increase in apoptosis. Oxymatrine also suppressed the migration and invasion of SW962 and A431 cells by reducing levels of MMP2 and MMP9. After treatment with oxymatrine or a RAS inhibitor (salirasib), expression levels of RAS, p-RAF, p-MEK, p-ERK, C-MYC, and MMP2 were reduced. When TGF-β1 was used to stimulate SW962 and A431 cells, the expression of the above proteins increased; this increase was reversed by using oxymatrine or salirasib again. Conclusion Oxymatrine inhibits proliferation and migration of VSCC cells by blocking the RAS/RAF/MEK/ERK pathway.
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2023
·Vol. 18
·期 2
·e0281845
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IF 3.7
Hao Tang,Shida Zhu,Kai Chen,Shujie Yuan,Junzu Hu,Hongkai Wang
Bone is a frequent target of tumor metastasis, with high incidence rate and poor prognosis. Osteoclasts play a key role in the process of tumor bone metastasis. Interleukin-17A (IL-17A) is an inflammatory cytokine, highly expressed in a variety of tumor cells, that can alter the autophagic activity of other cells, thereby causing corresponding lesions. Previous studies have shown that low concentration IL-17A can promote osteoclastogenesis. The aim of this study was to clarify the mechanism of low concentration IL-17A promoting osteoclastogenesis by regulating autophagic activity. The results of our study showed that IL-17A could promote the differentiation of osteoclast precursors (OCPs) into osteoclasts in the presence of RANKL, and increase the mRNA levels of osteoclast-specific genes. Moreover, IL-17A increased the expression of Beclin1 by inhibiting the phosphorylation of ERK and mTOR, leading to enhanced autophagy of OCPs, accompanied by decreased OCP apoptosis. Furthermore, knockdown of Beclin1 and suppression of autophagy by 3-methyladenine (3-MA) significantly attenuated the enhanced osteoclastogenesis induced by IL-17A. In summary, these results indicate that low concentration IL-17A enhances the autophagic activity of OCPs through the ERK/mTOR/Beclin1 pathway during osteoclastogenesis, and further promotes osteoclast differentiation, suggesting that IL-17A may serve as a potential therapeutic target for cancer-related bone resorption in cancer patients.
研究领域:
肿瘤学
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免疫学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cellular Reprogramming
·
2018
·Vol. 20
·期 2
·99-106
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IF 1.43
Mengya Zhao,Lin Li,Jundong Zhou,Xueyuan Cui,Qingmei Tian,Yaqing Jin,Yimin Zhu
Cancer stem cells (CSCs) are responsible for cancer initiating, recurrence, and drug resistance. Discovery of novel biomarkers for CSCs is helpful for early diagnosis and prognosis. Lung cancer stem cells (LCSCs) were closely related to the occurrence and development of lung cancer. In our study, the important role of miR-2861 in maintaining the stemness of LCSCs was investigated. The LCSC differentiation model was established through introducing serum into the medium of H460 spheres. miR-2861 expression was significantly higher in LCSCs no matter compared to the differentiation cells or normal cells. HDAC5 expression was positively correlated with miR-2861 in LCSCs, and knockdown of miR-2861 decreased the expression of HDAC5, which implied that HDAC5 may be involved in the differentiation of LCSCs mediated by miR-2861. The role of HDAC5 in the regulation of LCSC differentiation was further verified by the inhibitory effect of LMK-235 on the phosphorylation of ERK1/2, which was recognized as the regulator of CSC differentiation. Our study provided a better understanding of miR-2861 and HDAC5 axis in maintaining the stemness of LCSCs and laid a foundation for molecular targeted therapy.
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
Evidence-based Complementary and Alternative Medicine
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2015
·Vol. 2015
·期 1
·414965
·
IF 1.88
Chunxiao Wu,Jiao Wang,Chun Li,Guoping Zhou,Xiuhong Xu,Xin Zhang,Xiao Lan
Background . EA therapy is a traditional therapeutic approach for alleviation of cerebral I/R-induced brain injury. We investigated the effect of EA on MCAO rat model to examine the mechanism of apoptosis in the rat hippocampus. Methods . 200 male Sprague-Dawley rats were randomly divided into sham, I/R, EA, ERK inhibitor (PD), and ERK inhibitor+EA (PD+EA) groups. Each group was subdivided into 5 groups according to different time points. Locomotor behaviors were evaluated using neurological scales and morphological examination was performed using HE staining. Apoptosis index of neural cells in local infarcted area was measured by TUNEL and p-ERK expression was detected using immunohistochemistry technique and western blot analysis. Results . Neurological deficit scores and neural apoptosis in the EA group were lower than I/R group at the same time points, respectively. At different time points, p-ERK level was increased in the ischemic hippocampal CA1 in the EA group as compared to I/R group; the increased level was increased most at 1 day, 3 days, and 1 week ( p < 0.01). Conclusion . EA alleviates neurological deficit, reduces apoptosis index, and simultaneously upregulates the expression of p-ERK signal pathway in rats subjected to I/R injury.
研究领域:
神经生物学
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中西医结合
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分子医学
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脑血管病学
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针灸学
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DOI
高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
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2021
·Vol. 26
·期 1
·1-16
·
IF 5.787
Xing Ying,Liu Yang,Qi Zhong,Liu Zhengrong,Wang Xin,Zhang Hongyi
Background Hepatocellular carcinoma (HCC) is now the second leading cause of cancer death worldwide and lacks effectual therapy due to its high rate of tumor recurrence and metastasis. The aim of this study was to investigate the effects of L antigen family member 3 (LAGE3, a member of the LAGE gene family involved in positive transcription) on the progression of HCC. Methods The expression of LAGE3 was detected by quantitative real-time polymerase chain reaction. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation assay, EdU, and cell cycle analysis assay were employed to evaluate the proliferation of HCC cells. Annexin V-FITC/PI and TUNEL assay were used to assess the apoptosis rate of HCC cells. Wound healing and transwell assay were used to investigate the migration and invasion of HCC cells. A xenograft model of HCC was established with 2 × 10 6 Hep3B or SK-HEP1 cells to investigate the in vivo effects of LAGE3. Then, the protein levels of LAGE3, p-p38, p-38, c-Jun N-terminal kinase (JNK),p-JNK, extracellular signal-regulated kinase (ERK), and p-ERK were detected by western blot. Results We found that LAGE3 was upregulated in HCC tissues compared to adjacent tissues, and its high expression was correlated with poor overall survival by bioinformatics analysis. Next, we manually regulated the expression of LAGE3 in HCC cells. The knockdown of LAGE3 inhibited the proliferation of HCC cells by arresting the cell cycle in G1 phase. Also the downregulation of LAGE3 inhibited cell migration and invasion and induced apoptosis of HCC cells, while overexpression of LAGE3 promoted the malignant phenotypes of HCC. These results were further confirmed by the in vivo growth of HCC xenografts and the inhibition of apoptosis of HCC tumor cells. Furthermore, we found that LAGE3 exerted cancer-promoting effects by potentiating the JNK and ERK signaling pathway. An ERK inhibitor (10 μM SCH772984) or JNK inhibitor (25 μM SP600125) repressed the upregulated LAGE3-induced proliferation, migration, and invasion of HCC cells. Conclusions LAGE3 enhanced the malignant phenotypes of HCC by promoting the JNK and ERK signaling pathway.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
·
IF 4.8
Li-Ying Han,Hao Yu,Shuai Wang,Yong-Rui Bao,Tian-Jiao Li,Ying Zheng,Xi Luo,Meng-Nan Jia,Qiang Zhang,Xian-Sheng Meng
Ethnopharmacological relevance Colorectal cancer (CRC) belongs to the category of intestinal wind, anal ulcer, abdominal mass and other diseases in traditional Chinese medicine (TCM). Floris Sophorae Powder (F.S), is a classical prescription is recorded in Puji Benshi Fang for the treatment of intestinal carbuncle. It has been incorporated into the prescriptions for the treatment of intestinal diseases and achieved remarkable results in modern medicine. However, the mechanism of F.S in the treatment of colorectal cancer remains unclear and requires further study. Aim of the study To investigate F.S in treating CRC and clarify the underlying mechanism. Materials and methods This study was based on Dextran Sulfate Sodium Salt (DSS) combined with Azoxymethane (AOM) induced CRC mouse model to clarify the pharmacological effects of F.S. The serum metabolomics was used to study the mechanism of action, and the chemical composition of F.S was found by UPLC-Q-TOF-MS. The rationality of serm metabolomics results was verified through the clinical target database of network pharmacology, and the upstream and downstream targets of related pathways were found. The mechanism pathway was verified by Western blot to clarify its mechanism of action. Results In vivo pharmacological experiments showed that F.S inhibited tumor growth and improved hematochezia. The vital signs of mice in the high-dose F.S group approached to those in the control group. A total of 43 differential metabolites were found to be significantly changed by serum metabolomics. F.S could modulate and recover most of the differential metabolites, which proved to be closely related to the KRAS/MEK-ERK signaling pathway. A total of 46 compounds in F.S were identified, and the rationality of serm metabolic pathway was verified by network pharmacology. Western blot results also verified that the expression of KRAS, E2F1, p-MEK and p-ERK were significantly decreased after F.S treatment. Conclusion Classical prescription Floris Sophorae Powder treat colorectal cancer by regulating KRAS/MEK-ERK signaling pathway.
研究领域:
药理学
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肿瘤学
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中医
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代谢组学
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信号转导
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2019
·Vol. 235
·期 3
·2847-2856
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IF 4.522
Jiabing Zhang,Leili Wang,Wei Xie,Shunying Hu,Hao Zhou,Pingjun Zhu,Hang Zhu
Septic cardiomyopathy is associated with mitochondrial damage and endoplasmic reticulum (ER) dysfunction. However, the upstream mediator of mitochondrial injury and ER stress has not been identified and thus little drug is available to treat septic cardiomyopathy. Here, we explored the role of B-cell receptor-associated protein 31 (BAP31) in septic cardiomyopathy and figure out whether melatonin could attenuate sepsis-mediated myocardial depression via modulating BAP31. Lipopolysaccharide (LPS) was used to establish the septic cardiomyopathy model. Pathway analysis was performed via western blot, quantitative polymerase chain reaction and immunofluorescence. Mitochondrial function and ER stress were detected via enzyme-linked immunosorbent assay, western blot, and immunofluorescence. After exposure to LPS, cardiac function was reduced due to excessive inflammation response and extensive cardiomyocyte death. Mechanistically, melatonin treatment could dose-dependently improve cardiomyocyte viability via preserving mitochondrial function and reducing ER stress. Further, we found that BAP31 transcription was repressed by LPS whereas melatonin could restore BAP31 expression; this effect was dependent on the MAPK-ERK pathway. Inhibition of the ERK pathway and/or knockdown of BAP31 could attenuate the beneficial effects of melatonin on mitochondrial function and ER homeostasis under LPS stress. Altogether, our results indicate that ERK-BAP31 pathway could be used as a critical mediator for mitochondrial function and ER homeostasis in sepsis-related myocardial injury. Melatonin could stabilize BAP31 via the ERK pathway and thus contribute to the preservation of cardiac function in septic cardiomyopathy.
研究领域:
心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 37
·期 9
·2201-2213
·
IF 4.109
Qi Xiong,Xiang Tian,Congyue Xu,Baomiao Ma,Wei Liu,Binlian Sun,Qin Ru,Xiji Shu
PM 2.5 exposure has been demonstrated to correlate with neurological disorders recently. Ferroptosis is recognized as a newly found programmed form of cell death associated with neurodegenerative diseases, while glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis. However, the relationship between PM 2.5 -induced neurotoxicity and ferroptosis is still unclear. The current study aims to investigate if ferroptosis is involved in neurotoxicity post PM 2.5 exposure and its underlying mechanism. The PM 2.5 -treated neuronal Neuro-2a (N2A) and SH-SY5Y cells were applied to the current study. The results showed that PM 2.5 significantly increased the neuronal cell death, yet the ferroptosis antagonist Ferrostain-1 (Fer-1) markedly decreased the cell death induced by PM 2.5 . Western blot further confirmed that ferroptosis was triggered post PM 2.5 treatment in N2A cells by decreasing expressions of GPX4 and ferritin heavy chain (FTH), as well as enhancing expressions of ferritin light chain (FTL) and transferrin receptor protein (TFRC). Meanwhile, PM 2.5 treatment augmented neuronal oxidative damage and mitochondrial dysfunction. The bioinformatic analysis indicated that CREB could be the regulator of GPX4, and our results showed that ERK/CREB pathway was down-regulated in N2A cells post PM 2.5 treatment. The addition of ERK1/2 agonist post PM 2.5 treatment significantly inhibit ferroptosis via increasing the expression of GPX4. Taken together, the present study demonstrated that PM 2.5 -induced ferroptosis via inhibiting ERK/CREB pathway, and these findings will advance our knowledge of PM 2.5 -induced cytotoxicity in the nervous system.
研究领域:
神经科学
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毒理学
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细胞生物学
·
环境健康
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DOI
PubMed
高影响因子
Molecular Cancer
·
2022
·Vol. 21
·期 1
·1-17
·
IF 41.444
Pan Zhenzhen,Wang Kai,Wang Xiniao,Jia Zhirong,Yang Yuqi,Duan Yalei,Huang Lianzhan,Wu Zhuo-Xun,Zhang Jian-ye,Ding Xuansheng
Background The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance.Methods EGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay.Results Long-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo.Conclusion sOur study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of 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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产品关联
DOI
PubMed
高影响因子
American Journal of Translational Research
·
2021
·
IF 4.06
Lingli Huang,Di Xiao,Tianyu Wu,Xin Hu,Jun Deng,Xinjian Yan,Jingtao Wu,Simeng Xu,Xiaoping Yang,Gaofeng Li
Sorafenib is a first-line drug to treat advanced hepatocellular carcinoma (HCC), which can prolong the median overall survival of patients by approximately 3 months. Phenformin is a biguanide derivative that has been shown to exhibit antitumor activity superior to that of metformin. We herein explored the ability of phenformin to enhance the anti-cancer activity of sorafenib against HCC and the mechanisms underlying such synergy. The Hep-G2 and SMMC-7721 HCC cell lines were treated with sorafenib and/or phenformin, after which the proliferation of these cells was evaluated via MTT and colony formation assays, while invasion and apoptotic cell death were evaluated via Transwell and flow cytometry assays, respectively. In addition, protein levels were assessed by Western blotting, drug synergy was assessed with the CompuSyn software, and xenograft models were established by implanting Hep-G2 cells into nude mice and then assessing drug antitumor efficacy. Sorafenib and phenformin exhibited a synergistic ability to suppress HCC cell proliferation, migration, and survival. Phenformin further bolstered the ability of sorafenib to inhibit the CRAF/ERK and PI3K/AKT/mTOR pathways. Strikingly, the combination of these two drugs achieved better in vivo efficacy in a murine model system, without causing significant weight loss or hepatorenal toxicity. Sorafenib and phenformin can synergistically suppress CRAF/ERK and PI3K/AKT/mTOR pathway activation in HCC cells, and may thus represent a promising approach to treating this deadly cancer.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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