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Effect of cryptotanshinone (CT) on hypoxia-induced HIF-1α activation in PC-3 cells. (a) Chemical structure of CT. (b) Effect of CT on the viability of prostate cancer cells under normoxia and hypoxia. (c) Effect of HIF-1α accumulation in hypoxic PC-3 cells. Cells were treated with CT (10 μM) for 0.5, 2, 4, 6, and 24 h under hypoxia and Western blotting was performed. (d) Effect of CT on HIF-1α transcriptional activity in hypoxic PC-3 cells by ELISA. Cells were treated with or without CT (5 or 10 μM) under normoxia or hypoxia for 6 h and HIF-1α transcriptional activity was evaluated by TransAM HIF-1 transcriptional factor assay kit. Data represent means ± S.D. ##P < 0.01 versus normoxia control. *P < 0.05 or **P < 0,01 versus hypoxia control. (e) Effect of CT on HIF-1α nuclear translocation in hypoxic PC-3 cells. Cells treated with or without CT (10 μM) under hypoxia for 6 h were fixed with 10% formalin for immunocytochemistry fluorescence staining. Green color was detected for HIF-1α in PC-3 cells, while nuclei were counterstained with blue color using DAPI.
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Although cryptotanshinone (CT) was known to exert antitumor activity in several cancers, its molecular mechanism under hypoxia still remains unclear. Here, the roles of AEG-1 and HIF-1α in CT-induced antitumor activity were investigated in hypoxic PC-3 cells. CT exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation a...
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Background:
The objective of this study was to examine the prognostic significance of carbonic anhydrase IX (CAIX), an endogenous marker for tumor hypoxia; the cellular tumor antigen p53; and the apoptosis regulator Bcl-2, in triple-negative breast cancer (TNBC) patients.
Methods:
Immunohistochemically determined expression of CAIX, p53, Bcl-2 a...
Tumor hypoxia is associated with malignant progression and treatment resistance. Hypoxia-related factors, such as carbonic anhydrase IX (CA IX), glucose transporter-1 (GLUT-1), and vascular endothelial growth factor (VEGF) permit tumor cell adaptation to hypoxia. We attempted to elucidate the correlation of these markers with variable clinicopathol...
Tumor hypoxia is significant in promoting tumor progression and resistance to therapy, and hypoxia-inducible factor 1α (HIF-1α) is essential in the adaptive response of cells to hypoxia. The aim of the present study was to investigate the expression of hypoxic markers and evaluate their prognostic significance in soft tissue sarcoma (STS). A retros...
Citations
... Targeting oncogenes at the gene or protein level with highly selective inhibitors is a promising cancer treatment and drug development field. Metadherin (MTDH), also known as Lysine-Rich CEACAM1 Co-Isolated Protein (LYRIC) or Astrocyte Elevated Gene-1 Protein (AEG-1), is an oncogene encoding MTDH protein that promotes various cancers 3 , including breast 4 , prostate 5 , liver 6 , lung 7 , glioma 8 , cervical 9 , bladder 10 , kidney 11 , gastric 12 , colorectal 13 , and head and neck cancers 14 . Bioinformatic analysis showed that MTDH is overexpressed in various cancers and correlates with poor prognosis 15,16 . ...
p class="MsoNormal" style="margin-top: 12pt; text-align: justify;"> Metadherin (MTDH), also known as LYRIC or AEG-1, is an oncogene that enhances tumor progression, metastasis, drug resistance, and immune escape in various cancers by modulating multiple oncogenic pathways, including NF-κB, PI3K/AKT, Wnt/β-catenin, MAPK, and AMPK . Due to the unknown of the complete structure of MTDH, the deep mechanisms of MTDH and selective inhibitors targeting MTDH remain to be explored. The Protein-Protein interaction (PPI) with the Staphylococcal nuclease domain containing 1 (SND1) is a crucial mechanism underlying the function of MTDH. Current studies have demonstrated that inhibitors, including antisense oligonucleotides, peptides, and small molecules targeting MTDH or MTDH-SND1 interactions, provide novel strategies to inhibit the oncogenetic effects of MTDH. This review summarizes and discusses the structure, function, and regulation of MTDH in cancers, providing the potential therapeutic perspectives of MTDH or MTDH-SND1 PPI for drug discovery. </p
... in the present study, the decreased expression of VeGF following cT treatment may partially be due to the inhibition of HIF-1α expression, limiting binding of HIF-1α to the VEGF promoter region (51). This may partially reduce the formation of new blood vessels caused by hypoxia, thus playing a therapeutic role in wet age-related macular degeneration, which is characterized by aberrant angiogenesis (52). ...
The development of several retinal diseases is closely related to hypoxia. As a component of the Traditional Chinese medicine Salvia miltiorrhiza, the effects of cryptotanshinone (CT) on retinal cells under hypoxic conditions are not well understood. The aim of the present study was to explore how CT exerted its protective effects on retinal pigment epithelium (RPE) cells under hypoxic conditions induced by cobalt chloride (CoCl2). The effects of CT were investigated using a Cell Counting Kit‑8 assay, Annexin V‑FITC/PI staining, reverse transcription‑quantitative PCR and western blotting in ARPE‑19 cells. CT (10 and 20 µM) reduced the CoCl2‑induced increase in vascular endothelial growth factor expression and hypoxia‑inducible transcription factor‑1α expression in ARPE‑19 cells. Additionally, CT alleviated hypoxia‑induced apoptosis by regulating Bcl‑2 and Bax protein expression. CT treatment also reduced the increase in the mRNA levels of IL‑6, IL‑1β and TNF‑α induced by CoCl2. In summary, CT may protect RPE cells against apoptosis and inflammation in CoCl2‑induced hypoxia, and these results warrant further in vivo study into its value as a drug for treating hypoxic eye diseases.
... Astrocyte elevated gene-1 (AEG-1)/Lysine-rich CEACAM1 co-isolated protein (LYRIC) in humans is encoded by gene metadherin (MTDH); mapped in chromosome 8q22 is a prime oncogene, constituting about 528 amino acids, two nuclear localization sequences, an N terminal transmembrane region, a possible ATP or GTP-binding site and several putative phosphorylation sites [1], which is markedly overexpressed in several cancer types [2] as in esophageal squamous cell (ESCC) [3], gastric [4], colorectal [5], hepatocellular (HCC) [6,7], breast [8], prostate [9] and osteosarcoma [10]. AEG-1 helps in the and several putative phosphorylation sites [1], which is markedly overexpressed in several cancer types [2] as in esophageal squamous cell (ESCC) [3], gastric [4], colorectal [5], hepatocellular (HCC) [6,7], breast [8], prostate [9] and osteosarcoma [10]. ...
... Astrocyte elevated gene-1 (AEG-1)/Lysine-rich CEACAM1 co-isolated protein (LYRIC) in humans is encoded by gene metadherin (MTDH); mapped in chromosome 8q22 is a prime oncogene, constituting about 528 amino acids, two nuclear localization sequences, an N terminal transmembrane region, a possible ATP or GTP-binding site and several putative phosphorylation sites [1], which is markedly overexpressed in several cancer types [2] as in esophageal squamous cell (ESCC) [3], gastric [4], colorectal [5], hepatocellular (HCC) [6,7], breast [8], prostate [9] and osteosarcoma [10]. AEG-1 helps in the and several putative phosphorylation sites [1], which is markedly overexpressed in several cancer types [2] as in esophageal squamous cell (ESCC) [3], gastric [4], colorectal [5], hepatocellular (HCC) [6,7], breast [8], prostate [9] and osteosarcoma [10]. AEG-1 helps in the progression and development of these cancers, and further, it was found that AEG-1 is necessitate in tissue proliferation, angiogenesis, invasion, metastasis and in reducing chemo-and radio-resistance. ...
... Following the analysis of laryngeal cancer, miR-448 exhibited restriction of cell migration, proliferation and other metastatic conditions [136] and in the case of malignant glioblastoma, the compound DYT-40 has reported to activate the mitochondrial apoptosis pathway hence inhibiting AEG-1 [137]. Other than miRNAs, a wide variety of natural compounds such as Cryptotanshinone and PB0412-3 (PB3) restricted metastasis in hypoxic prostate cancer and brain tumour respectively [9,138]. Currently, RNA silencing (siRNA) has proven to be effective in inhibition of AEG-1 as exhibited by the vector based short hairpin RNA (shRNA) in pancreatic cancer [139] and RNAi as revealed in cervical cancer [140]. ...
Tumor breakthrough is driven by genetic or epigenetic variations which assist in initiation, migration, invasion and metastasis of tumors. Astrocyte elevated gene-1 (AEG-1) protein has risen recently as the crucial factor in malignancies and plays a potential role in diverse complex oncogenic signaling cascades. AEG-1 has multiple roles in tumor growth and development and is found to be involved in various signaling pathways of: (i) Ha-ras and PI3K/AKT; (ii) the NF-κB; (iii) the ERK or mitogen-activated protein kinase and Wnt or β-catenin and (iv) the Aurora-A kinase. Recent studies have confirmed that in all the hallmarks of cancers, AEG-1 plays a key functionality including progression, transformation, sustained angiogenesis, evading apoptosis, and invasion and metastasis. Clinical studies have supported that AEG-1 is actively intricated in tumor growth and progression which includes esophageal squamous cell, gastric, colorectal, hepatocellular, gallbladder, breast, prostate and non-small cell lung cancers, as well as renal cell carcinomas, melanoma, glioma, neuroblastoma and osteosarcoma. Existing studies have reported that AEG-1 expression has been induced by Ha-ras through intrication of PI3K/AKT signaling. Conversely, AEG-1 also activates PI3K/AKT pathway and modulates the defined subset of downstream target proteins via crosstalk between the PI3K/AKT/mTOR and Hedgehog signaling cascade which further plays a crucial role in metastasis. Thus, AEG-1 may be employed as a biomarker to discern the patients of those who are likely to get aid from AEG-1-targeted medication. AEG-1 may play as an effective target to repress tumor development, occlude metastasis, and magnify the effectiveness of treatments. In this review, we focus on the molecular mechanism of AEG-1 in the process of carcinogenesis and its involvement in regulation of crosstalk between the PI3K/AKT/mTOR and Hedgehog signaling. We also highlight the multifaceted functions, expression, clinicopathological significance and molecular inhibitors of AEG-1 in various cancer types.
... Moreover, CPT can interfere with energy and material metabolism in tumor cells, induce Drp1, promote the transport of Bax from the cytosol to mitochondria, and disrupt mitochondria, thereby inhibiting the growth of osteosarcoma cells [31]. It can activate the reactive oxygen species (ROS) mitochondrial apoptosis pathway to induce melanoma cell apoptosis and prevent cell migration and invasion [32], and inhibit the accumulation of HIF-1α and the expression of AEG-1 in hypoxic prostate cancer cells, as well as having cytotoxic effects on prostate cancer cells [33]. When acting on ovarian cancer cells, it can cause the expression of glycolysis-related proteins, such as GLUT1, LDHA, and HK2, and inhibit glucose uptake and lactate production [20]. ...
Cryptotanshinone (IUPAC name: (R)-1,2,6,7,8,9-hexahydro-1,6,6-trimethyl-phenanthro(1,2-b)furan-10,11-dione), a biologically active constituent extracted from the roots and rhizomes of the plant Salvia miltiorrhiza, has been studied in depth as a medicinally active compound and shown to have efficacy in the treatment of numerous diseases and disorders. In this review, we describe in detail the current status of cryptotanshinone research, including findings relating to the structure, pharmacokinetics, pharmacological activity, and derivatives of this compound. Cryptotanshinoneh as a diverse range of pharmacological effects, including anti-cancer, anti-inflammatory, immune regulatory, neuroprotective, and anti-fibrosis activities. Studies on the molecular mechanisms underlying the activities of cryptotanshinone have established that the JAK2/STAT3, PI3K/AKT, NF-κB, AMPK, and cell cycle pathways are involved in the inhibitory and pro-apoptotic effects of cryptotanshinone on different tumor cell lines, these molecular pathways interact in a coordinated manner to inhibit cell proliferation, migration and invasion,and induce transformation, autophagy, necrosis, and cellular immunity. The anti-inflammatory mechanisms of cryptotanshinone have been found to be associated with the TLR4-MyD88/PI3K/Nrf2 and TLR4-MyD88/NF-κB/MAPK pathways, whereasthe Hedgehog, NF-κB, and Nrf-2/HO-1 pathways are regulated by cryptotanshinone to reduce organ fibrosis, and its inhibitory effects on the PI3K/AKT-eNOS pathway have been linked to neuroprotective effects. Given the potential medicinal utility of cryptotanshinone, further research is needed to verify the efficacy and safety of this compound in clinical use, evaluate its pharmacological activity, and identify molecular targets.
... They proposed MTDH as a novel genetic biomarker to serve as an attractive molecular target for new anticancer agents to prevent PC cell progression and metastasis. High MTDH expression also was observed in another prostate cancer cell lines: LNCaP, DU145 [18,19]. ...
... Moreover, the possible signalling pathways in prostate cancer cell lines, in which MTDH might be involved and that can be potential therapeutic targets for antineoplastic agents, have been studied. Inhibition of the Mtdh expression proved to be one of the molecular events demonstrating an antineoplastic effect [19]. In order to implement MTDH expression as a prognostic factor, further studies with consistent results are needed -gene expression analysis using digital droplet PCR and measurement of the potential biomarker in plasma or urine collected from prostate cancer's patients -should also be taken into account. ...
... Subsequently similar results were reported in lung cancer cells (A549), where the authors found that UA suppressed the expression level of AEG-1/MTDH/LYRIC by repressing nuclear factor-κB signaling (Liu, Guo, et al., 2013). In prostate cancer (Lee et al., 2012), cryptotanshinone was shown to exert its anticancer effects by inhibiting AEG-1/MTDH/LYRIC and HIF-1α. In breast cancer cells, cadmium chloride induced cell death by reducing AEG-1/MTDH/ LYRIC expression and NF-κB activity (Luparello, Longo, & Vetrano, 2012). ...
Since its original discovery in 2002, AEG-1/MTDH/LYRIC has emerged as a primary regulator of several diseases including cancer, inflammatory diseases, and neurodegenerative diseases. AEG-1/MTDH/LYRIC has emerged as a key contributory molecule in almost every aspect of cancer progression, including uncontrolled cell growth, evasion of apoptosis, increased cell migration and invasion, angiogenesis, chemoresistance, and metastasis. Additionally, recent studies highlight a seminal role of AEG-1/MTDH/LYRIC in neurodegenerative diseases and obesity. By interacting with multiple protein partners, AEG-1/MTDH/LYRIC plays multifaceted roles in the pathogenesis of a wide variety of diseases. This review discusses the current state of understanding of AEG-1/MTDH/LYRIC regulation and function in cancer and other diseases with a focus on its association/interaction with several pivotal protein partners.
... Consistent with previous reports in HepG2, MCF-7, PC-3, Du145 cells [19,29,30], we found that CTS dramatically inhibited the proliferation of A549 and 95D cells. The IC50s at micromolar level suggested that it was a potent anticancer compound, which was further confirmed by in vivo experiments performed here and previous reports [18,25,31]. Furthermore, CTS induced significant LDH release suggesting that the integrity of cell membrane was damaged by CTS. ...
... The in vivo anticancer effect of CTS has been accumulated [25,31]. The proposed mechanisms include: inhibition of HIF-1α, AEG1, and VEGF [31], androgen receptor and STAT3 [18,30], suppression of mTOR-mediated cyclin D1 expression and Rb phosphorylation [17]. ...
... The in vivo anticancer effect of CTS has been accumulated [25,31]. The proposed mechanisms include: inhibition of HIF-1α, AEG1, and VEGF [31], androgen receptor and STAT3 [18,30], suppression of mTOR-mediated cyclin D1 expression and Rb phosphorylation [17]. In present study, we showed that CTS had approximately equal efficacy in inhibiting the growth of A549 cells to that of PC-3 cells in vivo models [31]. ...
Cryptotanshinone (CTS), a natural product isolated from Salvia miltiorrhiza Bunge, demonstrates anticancer effect. Previous reports showed that CTS induced caspase-independent cell death. Here, we reported that CTS induced pro-death autophagy in human lung cancer cells. CTS inhibited the proliferation of A549 cells in a time- and concentration- dependent manner. CTS triggered autophagy as confirmed by monodansylcadaverine staining, transmission electron microscopy analysis, as well as western blot detection of microtubule-associated protein light-chain 3 (LC3). CTS induced intracellular reactive oxygen species (ROS) formation in a concentration- and time-dependent manner, which was reversed by N-acetyl-L-cysteine (NAC), catalase, diphenyleneiodonium (DPI), pyrrolinodimethylthiocarbamate (PDTC), and dicumarol. Furthermore, CTS-induced autophagy was inhibited by NAC, JNK siRNA and SP600125. NAC reversed CTS-induced JNK phosphorylation. NAC, 3-methyladenine (3-MA), and SP600125 partly reversed CTS-induced cell death. In addition, CTS (10 mg/kg) dramatically inhibited tumor growth by 48.3% in A549 xenograft nude mice, which was completely reversed by NAC (50 mg/kg) co-treatment. Our findings showed that CTS induced pro-death autophagy through activating JNK signaling mediated by increasing intracellular ROS production.
... Recently angiogenesis inhibitors [21][22][23][24] from natural products are attractive, though not powerful, with less side effects such as fetal development, bleeding, blood clot, hypertension, and protein in urine [25,26]. Our team also reported potent antiangiogenic materials from natural products, such as STB-HO [27], beta-sitosterol [28], cryptotanshinone [29], and emodin [30]. ...
Though dietary azuki bean (
Vigna angularis
) seed containing antioxidant proanthocyanidins was known to have multibiological activities including antioxidant, hypotensive, anti-inflammatory, and immunomodulatory activities, the antiangiogenic activity of ethanol extract of
Vigna angularis
(EVA) was never reported so far. In the present study, the antiangiogenic mechanism of EVA was examined in human umbilical vein endothelial cells (HUVECs). EVA showed weak cytotoxicity in HUVECs, while it significantly suppressed the VEGF induced proliferation of HUVECs. Consistently, wound healing assay revealed that EVA inhibited the VEGF induced migration of HUVECs. Also, EVA abrogated the VEGF induced tube formation of HUVECs in a concentration dependent fashion. Furthermore, Matrigel plug assay showed that EVA significantly reduced the hemoglobin level of Matrigel plug in mice compared to untreated control. Of note, EVA effectively attenuated the phosphorylation of VEGFR2, Erk, and Akt in VEGF-treated HUVECs. Overall, our findings suggest that EVA inhibits angiogenesis in VEGF-treated HUVECs via inhibition of phosphorylation of VEGFR2, ERK, and Akt.
... In 2012, Lee et al. investigated the roles of AEG-1 (astrocyte elevated gene 1) and HIF-1α in cryptotanshinone-induced antitumor activity in hypoxic PC-3 cells [65]. They suggested that cryptotanshinone exerted its antitumor activity via the inhibition of HIF-1α, AEG1, and VEGF as a potent chemotherapeutic agent. ...
... Quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blotting showed that the expression level of MTDH in prostate cancer cells was nearly three times higher compared to those in non-cancerous human prostatic epithelial cell line (RWPE-1 cells) at the mRNA and protein level, respectively. High MTDH expressions were found in three common prostate cancer cells lines|: LNCaP, DU145 and PC-3 cell lines (23,24). ...
... In addition, these results also prove that the inhibition of prostate cancer progression by MTDH knockdown may be mediated by suppression of AKT and upregulation of FOXO3a activity (23). In hypoxic PC-3 cells, MTDH may participate in the downstream of the hypoxia-inducible factor 1α (HIF-1α) or phosphoinositide 3-kinase pathways (24). ...
... The signaling pathways of MTDH were reviewed systematically in prostate cancer previously in this study and it was concluded that MTDH may be a target in the treatment of prostate cancer. In order to investigate the molecular mechanism of cryptotanshinone in anticancer, several genes were analyzed in the study by Lee et al (24), including MTDH and HIF-1α. Inhibition of MTDH expression was found to be one of the molecular targets for cryptotanshinone exerting anticancer effects (24). ...
Metadherin (MTDH) has been identified as an important oncogene in carcinogenesis, tumor progression and metastasis in numerous malignancies, through signal transduction pathways. MTDH is a potential biomarker and therapeutic target in cancers. The present systematic review was performed to search for studies regarding MTDH and prostate, bladder and kidney cancer using several databases and the eligible studies were reviewed. MTDH expression was found to significantly increase in prostate, bladder and kidney cancers, not only in clinical tissue samples, but also in cancer cell lines. Reviewing the clinical and statistical analysis revealed that MTDH may be involved in urologic cancer progression, metastasis and prognosis. MTDH may be an independent or one of the cofactors in urologic cancers for prediction of patient survival, and may be involved in potential anticancer strategies. MTDH may be associated with several signal transduction pathways in urologic cancers, indicating latent targets to develop anticancer therapeutic strategy. Further studies are required to confirm these findings.
