Ginseng saponin metabolite 20(S)-protopanaxadiol inhibits tumor growth by targeting multiple cancer signaling pathways

Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its effect against in vivo tumor promoting activity has not been reported yet. Therefore, this study was aimed to investigate antitumor-promoting activity of annonacin via in vivo two-stage mouse skin tumorigenesis model and its molecular pathways involved. Annonacin 85 nM was topically applied to DMBA/TPA-induced ICR mice for 22 weeks of treatment. Histopathological examination of skin, liver and kidney as well as genes and proteins expression analysis were conducted. Annonacin significantly increased the tumor latency period and also reduced the tumor incidence, tumor burden and tumor volume, respectively. In addition, it also suppressed tumorigenesis manifested by significant reduction of hyperkeratosis, dermal papillae and number of keratin pearls on skin tissues. Annonacin also appeared to be non-toxic to liver and kidney. Significant modulation of both AKT, ERK, MTOR, p38, PTEN and Src genes and proteins were also observed in annonacin-targeted signaling pathway(s) against tumorigenesis. Collectively, results of this study indicate that annonacin is a potential therapeutic compound targeting tumor promoting stage in skin tumorigenesis by modulating multiple gene and protein in cancer signaling pathways without apparent toxicity.

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Extracts from Pulsatilla patens target cancer-related signaling pathways in HeLa cells

Scientific Reports ◽

10.1038/s41598-021-90136-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Grażyna Łaska ◽

Magdalena Maciejewska-Turska ◽

Elwira Sieniawska ◽

Łukasz Świątek ◽

David S. Pasco ◽

...

Keyword(s):

Signaling Pathways ◽

Hela Cells ◽

Luciferase Reporter ◽

Cervical Cancer Cell Line ◽

Phytochemical Analysis ◽

Root Extract ◽

Triterpenoid Saponins ◽

Cancer Signaling ◽

Methanolic Extracts ◽

Pulsatilla Patens

AbstractThe purpose of this study was to determine if a methanolic extract of the Pulsatilla patens (L.) Mill. can inhibit the progression of cancer through the modulation of cancer-related metabolic signaling pathways. We analyzed a panel of 13 inducible luciferase reporter gene vectors which expression is driven by enhancer elements that bind to specific transcription factors for the evaluation of the activity of cancer signaling pathways. The root extract of P. patens exhibited strong inhibition of several signaling pathways in HeLa cells, a cervical cancer cell line, and was found to be the most potent in inhibiting the activation of Stat3, Smad, AP-1, NF-κB, MYC, Ets, Wnt and Hdghog, at a concentration of 40 µg/mL. The methanolic extracts of P. patens enhanced apoptotic death, deregulated cellular proliferation, differentiation, and progression towards the neoplastic phenotype by altering key signaling molecules required for cell cycle progression. This is the first study to report the influence of Pulsatilla species on cancer signaling pathways. Further, our detailed phytochemical analysis of the methanolic extracts of the P. patens allowed to deduce that compounds, which strongly suppressed the growth and proliferation of HeLa cancer cells were mainly triterpenoid saponins accompanied by phenolic acids.

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CBP/p300: Critical Co-Activators for Nuclear Steroid Hormone Receptors and Emerging Therapeutic Targets in Prostate and Breast Cancers

Cancers ◽

10.3390/cancers13122872 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2872

Author(s):

Aaron R. Waddell ◽

Haojie Huang ◽

Daiqing Liao

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Tumor Growth ◽

Signaling Pathways ◽

Cell Cycle Progression ◽

Hormone Receptors ◽

Steroid Hormone Receptors ◽

Breast Cancers ◽

Creb Binding Protein ◽

Breast And Prostate Cancer

The CREB-binding protein (CBP) and p300 are two paralogous lysine acetyltransferases (KATs) that were discovered in the 1980s–1990s. Since their discovery, CBP/p300 have emerged as important regulatory proteins due to their ability to acetylate histone and non-histone proteins to modulate transcription. Work in the last 20 years has firmly established CBP/p300 as critical regulators for nuclear hormone signaling pathways, which drive tumor growth in several cancer types. Indeed, CBP/p300 are critical co-activators for the androgen receptor (AR) and estrogen receptor (ER) signaling in prostate and breast cancer, respectively. The AR and ER are stimulated by sex hormones and function as transcription factors to regulate genes involved in cell cycle progression, metabolism, and other cellular functions that contribute to oncogenesis. Recent structural studies of the AR/p300 and ER/p300 complexes have provided critical insights into the mechanism by which p300 interacts with and activates AR- and ER-mediated transcription. Breast and prostate cancer rank the first and forth respectively in cancer diagnoses worldwide and effective treatments are urgently needed. Recent efforts have identified specific and potent CBP/p300 inhibitors that target the acetyltransferase activity and the acetytllysine-binding bromodomain (BD) of CBP/p300. These compounds inhibit AR signaling and tumor growth in prostate cancer. CBP/p300 inhibitors may also be applicable for treating breast and other hormone-dependent cancers. Here we provide an in-depth account of the critical roles of CBP/p300 in regulating the AR and ER signaling pathways and discuss the potential of CBP/p300 inhibitors for treating prostate and breast cancer.

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Crosstalk between MUC1 and VEGF in angiogenesis and metastasis: a review highlighting roles of the MUC1 with an emphasis on metastatic and angiogenic signaling

Cancer Cell International ◽

10.1186/s12935-021-01899-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Farnaz Khodabakhsh ◽

Parnaz Merikhian ◽

Mohammad Reza Eisavand ◽

Leila Farahmand

Keyword(s):

Tumor Growth ◽

Signaling Pathways ◽

Cell Fate ◽

Endothelial Cell Proliferation ◽

Mucin 1 ◽

Signaling Transduction ◽

Growth And Survival ◽

Angiogenic Proteins ◽

Angiogenic Effect ◽

And Migration

AbstractVEGF and its receptor family (VEGFR) members have unique signaling transduction system that play significant roles in most pathological processes, such as angiogenesis in tumor growth and metastasis. VEGF-VEGFR complex is a highly specific mitogen for endothelial cells and any de-regulation of the angiogenic balance implicates directly in endothelial cell proliferation and migration. Moreover, it has been shown that overexpressing Mucin 1 (MUC1) on the surface of many tumor cells resulting in upregulation of numerous signaling transduction cascades, such as growth and survival signaling pathways related to RTKs, loss of cell-cell and cell-matrix adhesion, and EMT. It promotes gene transcription of pro-angiogenic proteins such as HIF-1α during periods of oxygen scarcity (hypoxia) to enhance tumor growth and angiogenesis stimulation. In contrast, the cytoplasmic domain of MUC1 (MUC1-C) inhibits apoptosis, which in turn, impresses upon cell fate. Besides, it has been established that reduction in VEGF expression level correlated with silencing MUC1-C level indicating the anti-angiogenic effect of MUC1 downregulation. This review enumerates the role of MUC1-C oncoprotein and VEGF in angiogenesis and metastasis and describes several signaling pathways by which MUC1-C would mediate the pro-angiogenic activities of cancer cells.

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Positive Crosstalk Between Hedgehog and NF-κB Pathways Is Dependent on KRAS Mutation in Pancreatic Ductal Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.652283 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yuqiong Wang ◽

Dan Wang ◽

Yanmiao Dai ◽

Xiangyu Kong ◽

Xian Zhu ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathways ◽

Kras Mutation ◽

Biological Effects ◽

Ductal Adenocarcinoma ◽

Luciferase Reporter ◽

Hh Signaling

It has been shown that aberrant activation of the Hedgehog (Hh) and nuclear factor-kappa B (NF-κB) signaling pathways plays an important role in the pancreatic carcinogenesis, and KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDAC). Until now, the role of KRAS mutation in the context of crosstalk between Hh and NF-κB signaling pathways in PDAC has not been investigated. This study was to determine whether the crosstalk between the Hh and NF-κB pathways is dependent on KRAS mutation in PDAC. The correlation between Gli1, Shh, NF-κB p65 expression and KRAS mutation in PDAC tissues was firstly examined by immunohistochemistry. Next, Western blotting, qPCR, and immunofluorescence were conducted to examine the biological effects of interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) as NF-κB signaling agonists, Shh as an Hh ligand alone or in combination with KRAS small interfering RNA (si-KRAS) in KRAS-mutant PDAC cells (MT-KRAS; SW1990 and Panc-1), wild-type KRAS PDAC cells (WT-KRAS; BxPC-3) and mutant KRAS knock-in BxPC-3 cells in vitro as well as tumor growth in vivo. KRAS mutation-dependent crosstalk between Hh and NF-κB in PDAC cells was further assessed by Ras activity and luciferase reporter assays. The aberrant Hh and NF-κB pathway activation was found in PDAC tissues with KRAS mutation. The same findings were confirmed in MT-KRAS PDAC cells and MT-KRAS knock-in BxPC-3 cells, whereas this activation was not observed in WT-KRAS PDAC cells. However, the activation was significantly down-regulated by KRAS silencing in MT-KRAS PDAC cells. Furthermore, MT-KRAS cancer cell proliferation and survival in vitro and tumor growth after inoculation with MT-KRAS cells in vivo were promoted by NF-κB and Hh signaling activation. The pivotal factor for co-activation of NF-κB and Hh signaling is MT-KRAS protein upregulation, showing that positive crosstalk between Hh and NF-κB pathways is dependent upon KRAS mutation in PDAC.

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“The Infinite Maze” of breast cancer, signaling pathways and radioresistance

The Breast ◽

10.1016/j.breast.2013.04.003 ◽

2013 ◽

Vol 22 (4) ◽

pp. 411-418 ◽

Cited By ~ 7

Author(s):

Orit Kaidar-Person ◽

Christine Lai ◽

Abraham Kuten ◽

Yazid Belkacemi

Keyword(s):

Breast Cancer ◽

Signaling Pathways ◽

Cancer Signaling

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Involvement of CD24 in Multiple Cancer Related Pathways Makes It an Interesting New Target for Cancer Therapy

Current Cancer Drug Targets ◽

10.2174/1570163814666170818125036 ◽

2018 ◽

Vol 18 (4) ◽

pp. 328-336 ◽

Cited By ~ 12

Author(s):

Shirin Eyvazi ◽

Bahram Kazemi ◽

Siavoush Dastmalchi ◽

Mojgan Bandehpour

Keyword(s):

Cancer Cells ◽

Signaling Pathways ◽

Src Kinases ◽

Invasion And Metastasis ◽

Multiple Cancer ◽

Exact Role ◽

Promote Cell Proliferation ◽

Downstream Effectors ◽

Cluster Of Differentiation

CD24 (cluster of differentiation 24) is a small heavy glycosylated protein, which is overexpressed in many cancer and some cancer stem cells and is associated with the development, invasion, and metastasis of cancer cells. The exact role of CD24 in these processes is not fully understood, however, in this article, it has been tried to present a collection of cancer-related mechanisms attributed to CD24. Based on the literature, CD24 dis-regulates different signaling pathways in various cancer cells, including; Src kinases, STAT3, EGFR, Wnt/β-catenin and MAPK. Src kinases play an important role in the signaling pathways which activate p38 MAPK and STAT3 pathways. Akt and ERK are downstream effectors of CD24-activated EGFR, which promote cell proliferation, invasion and metastasis. CD24 increases the expression of HER2 by the activation of NF-κB transcription factor. Moreover, CD24 up-regulates the expression of miR-21 oncomir through the activation of Src kinases. Identification of the details of these pathways and also new pathways will help researchers to explore new CD24 targeted therapies.

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Driver network as a biomarker: systematic integration and network modeling of multi-omics data to derive driver signaling pathways for drug combination prediction

Bioinformatics ◽

10.1093/bioinformatics/btz109 ◽

2019 ◽

Vol 35 (19) ◽

pp. 3709-3717 ◽

Cited By ~ 12

Author(s):

Lei Huang ◽

David Brunell ◽

Clifford Stephan ◽

James Mancuso ◽

Xiaohui Yu ◽

...

Keyword(s):

Signaling Pathways ◽

Cancer Patients ◽

Functional Module ◽

B Cell Lymphoma ◽

Drug Combinations ◽

Supplementary Information ◽

Gene Copy ◽

Omics Data ◽

Multiple Cancer ◽

Synergistic Drug Combinations

Abstract Motivation Drug combinations that simultaneously suppress multiple cancer driver signaling pathways increase therapeutic options and may reduce drug resistance. We have developed a computational systems biology tool, DrugComboExplorer, to identify driver signaling pathways and predict synergistic drug combinations by integrating the knowledge embedded in vast amounts of available pharmacogenomics and omics data. Results This tool generates driver signaling networks by processing DNA sequencing, gene copy number, DNA methylation and RNA-seq data from individual cancer patients using an integrated pipeline of algorithms, including bootstrap aggregating-based Markov random field, weighted co-expression network analysis and supervised regulatory network learning. It uses a systems pharmacology approach to infer the combinatorial drug efficacies and synergy mechanisms through drug functional module-induced regulation of target expression analysis. Application of our tool on diffuse large B-cell lymphoma and prostate cancer demonstrated how synergistic drug combinations can be discovered to inhibit multiple driver signaling pathways. Compared with existing computational approaches, DrugComboExplorer had higher prediction accuracy based on in vitro experimental validation and probability concordance index. These results demonstrate that our network-based drug efficacy screening approach can reliably prioritize synergistic drug combinations for cancer and uncover potential mechanisms of drug synergy, warranting further studies in individual cancer patients to derive personalized treatment plans. Availability and implementation DrugComboExplorer is available at https://github.com/Roosevelt-PKU/drugcombinationprediction. Supplementary information Supplementary data are available at Bioinformatics online.

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Curcumin inhibits cancer progression through regulating expression of microRNAs

Tumor Biology ◽

10.1177/1010428317691680 ◽

2017 ◽

Vol 39 (2) ◽

pp. 101042831769168 ◽

Cited By ~ 25

Author(s):

Siying Zhou ◽

Sijie Zhang ◽

Hongyu Shen ◽

Wei Chen ◽

Hanzi Xu ◽

...

Keyword(s):

Signaling Pathways ◽

Cancer Progression ◽

Noncoding Rna ◽

Target Genes ◽

Therapeutic Potential ◽

Tumor Biology ◽

Multiple Cancer ◽

Small Noncoding Rna ◽

Cancer Agent ◽

Regulation Of Cell Cycle

Curcumin, a major yellow pigment and spice in turmeric and curry, is a powerful anti-cancer agent. The anti-tumor activities of curcumin include inhibition of tumor proliferation, angiogenesis, invasion and metastasis, induction of tumor apoptosis, increase of chemotherapy sensitivity, and regulation of cell cycle and cancer stem cell, indicating that curcumin maybe a strong therapeutic potential through modulating various cancer progression. It has been reported that microRNAs as small noncoding RNA molecules are related to cancer progression, which can be regulated by curcumin. Dysregulated microRNAs play vital roles in tumor biology via regulating expressions of target genes and then influencing multiple cancer-related signaling pathways. In this review, we focused on the inhibition effect of curcumin on various cancer progression by regulating expression of multiple microRNAs. Curcumin-induced dysregulation of microRNAs may activate or inactivate a set of signaling pathways, such as Akt, Bcl-2, PTEN, p53, Notch, and Erbb signaling pathways. A better understanding of the relation between curcumin and microRNAs may provide a potential therapeutic target for various cancers.

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