MicroRNA-mutant P53 crosstalk in chemoresistance: a hint to monitor therapy outcome

: The chemoresistance of cancer cells is a multifactorial mechanism, in which de-regulated apoptotic pathways, the oxidative response and cancer cell migration play a crucial role. A key player in the control of such pathways is the tumor suppressor gene TP53, also defined as the “guardian of the genome”, encoding the P53 tetrameric transcription factor. P53, following cell injuries, can activate the transcription of several target genes crucial for the induction of apoptosis, cell cycle arrest, modulation of senescence, DNA repair, autophagy and metabolism. Importantly, TP53 gene is mutated in nearly 50% of human cancers, implying an altered expression of target genes in cancer cells. The presence of TP53 mutations can also affect the expression of several small non-coding RNAs (microRNAs or miRNAs), involved in the same regulation of the apoptotic signaling, cell cycle regulation and cell migration. In mutant P53 expressing tumors, some miRNAs resulted to be down-regulated, while others appeared to be up-regulated as demonstrated by in vitro and in vivo studies. Thus, the expression level of specific P53 responsive miRNAs could be used as a marker of cancer progression and therapy performance. In the present review, we will summarize the role of P53-related miRNAs and their clinical relevance in monitoring therapy outcome and progression of cancers with mutant P53.

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Involvement of the ERK/HIF-1α/EMT Pathway in XCL1-Induced Migration of MDA-MB-231 and SK-BR-3 Breast Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22010089 ◽

2020 ◽

Vol 22 (1) ◽

pp. 89

Author(s):

Ha Thi Thu Do ◽

Jungsook Cho

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Cancer Progression ◽

Chemokine Receptor ◽

Intracellular Signaling ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Mitogen Activated Protein Kinase ◽

Mesenchymal Transition

Chemokine–receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of X-C motif chemokine receptor 1 (XCR1), a specific receptor for chemokine X-C motif chemokine ligand 1 (XCL1), stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the exact mechanisms of this process remain to be elucidated. Our study found that XCL1 treatment markedly enhanced MDA-MB-231 cell migration. Additionally, XCL1 treatment enhanced epithelial–mesenchymal transition (EMT) of MDA-MB-231 cells via E-cadherin downregulation and upregulation of N-cadherin and vimentin as well as increases in β-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Notably, the effects of XCL1 on cell migration and intracellular signaling were negated by knockdown of XCR1 using siRNA, confirming XCR1-mediated actions. Treating MDA-MB-231 cells with U0126, a specific mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, blocked XCL1-induced HIF-1α accumulation and cell migration. The effect of XCL1 on cell migration was also evaluated in ER-/HER2+ SK-BR-3 cells. XCL1 also promoted cell migration, EMT induction, HIF-1α accumulation, and ERK phosphorylation in SK-BR-3 cells. While XCL1 did not exhibit any significant impact on the matrix metalloproteinase (MMP)-2 and -9 expressions in MDA-MB-231 cells, it increased the expression of these enzymes in SK-BR-3 cells. Collectively, our results demonstrate that activation of the ERK/HIF-1α/EMT pathway is involved in the XCL1-induced migration of both MDA-MB-231 and SK-BR-3 breast cancer cells. Based on our findings, the XCL1–XCR1 interaction and its associated signaling molecules may serve as specific targets for the prevention of breast cancer cell migration and metastasis.

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miR-335-5p Suppresses Gastric Cancer Progression by Targeting MAPK10

10.21203/rs.3.rs-52496/v1 ◽

2020 ◽

Author(s):

Yi Gao ◽

Yanfeng Wang ◽

Xiaofei Wang ◽

Changan Zhao ◽

Fenghui Wang ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Progression ◽

Target Gene ◽

Luciferase Reporter ◽

Gastric Cancer Cells ◽

Aberrant Expression ◽

Related Target

Abstract Background: In recent years, many microRNAs(miRNAs) involved in cancer progression. The aberrant expression of miR-335-5p in tumorigenesis has been demonstrated. The present study aimed to investigate the molecular mechanisms underlying miR-335-5p- regulated MAPK10 expression in human gastric cancer（GC）.Methods: The quantitative real-time PCR was used to study the level of miR-335-5p expression in gastric cancer cell lines and tissues. Subsequently, the MTT and cloning formation assays were used to detect cell proliferation, while transwell and wound-healing assays were used to identify invasion and migration of the gastric cancer cells. The correlation between the miR-335-5p and the cell cycle-related target gene mitogen‑activated protein kinase 10 (MAPK10) in gastric cancer was analyzed based on the website. In addition, the target gene of miR-335-5p was detected by luciferase reporter assay, qRT-PCR, and western blotting.Results: The miR-335-5p level was down-regulated in GC tissues and cell lines. Furthermore, miR-335-5p inhibited proliferation, migration of gastric cancer cells, and induced apoptosis. During the G1/S phase, miR-335-5p arrested the cycle of gastric cancer cells in vitro. The correlation between the miR-335-5p and the cell cycle-related target gene MAPK10 in GC was analyzed, MAPK10 was directly targeted by the miR-335-5p.Conclusion: These data suggested that miR-335-5p acts as a tumor suppressor, and go through the MAPK10 to inhibit the GC progression.

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Calcineurin regulates the stability and activity of estrogen receptor α

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2114258118 ◽

2021 ◽

Vol 118 (44) ◽

pp. e2114258118

Author(s):

Takahiro Masaki ◽

Makoto Habara ◽

Yuki Sato ◽

Takahiro Goshima ◽

Keisuke Maeda ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Target Genes ◽

Estrogen Receptor Α ◽

The Stability ◽

Positive Breast Cancer

Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to β-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118. Finally, the expression of the calcineurin A–α gene (PPP3CA) was associated with poor prognosis in ER-α–positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α–positive breast cancer.

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Ferruginol exhibits anticancer effects in OVCAR-3 human ovary cancer cells by inducing apoptosis, inhibition of cancer cell migration and G2/M phase cell cycle arrest

Molecular Medicine Reports ◽

10.3892/mmr.2017.7484 ◽

2017 ◽

Vol 16 (5) ◽

pp. 7013-7017 ◽

Cited By ~ 7

Author(s):

Wen-Dong Xiong ◽

Jian Gong ◽

Chao Xing

Keyword(s):

Cell Cycle ◽

Cell Migration ◽

Cancer Cells ◽

Phase Cell ◽

Cancer Cell Migration ◽

Human Ovary ◽

Cycle Arrest ◽

Anticancer Effects ◽

Apoptosis Inhibition ◽

M Phase

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PTEN-mediated G1 cell-cycle arrest in LNCaP prostate cancer cells is associated with altered expression of cell-cycle regulators

The Prostate ◽

10.1002/pros.21045 ◽

2009 ◽

Vol 70 (2) ◽

pp. 135-146 ◽

Cited By ~ 16

Author(s):

P.W. van Duijn ◽

A.C.J. Ziel-van der Made ◽

J.A.G. van der Korput ◽

J. Trapman

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Cell Cycle Regulators ◽

Prostate Cancer Cells ◽

Altered Expression ◽

Cycle Arrest ◽

G1 Cell Cycle Arrest

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Silymarin Enriched Extract (Silybum marianum) Additive Effect on Doxorubicin-Mediated Cytotoxicity in PC-3 Prostate Cancer Cells

Planta Medica ◽

10.1055/a-0954-6704 ◽

2019 ◽

Vol 85 (11/12) ◽

pp. 997-1007 ◽

Cited By ~ 3

Author(s):

Katerina Gioti ◽

Anastasia Papachristodoulou ◽

Dimitra Benaki ◽

Sophia Havaki ◽

Apostolos Beloukas ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cancer Cells ◽

Dependent Manner ◽

Prostate Cancer Cells ◽

Silybum Marianum ◽

Altered Expression ◽

Expression Levels ◽

Branched Chain

AbstractSilymarin-enriched extract (SEE) is obtained from Silybum marianum (Asteraceae). Doxorubicin (DXR) is a widely used chemotherapeutical yet with severe side effects. The goal of the present study was to assess the pharmacologic effect of SEE and its bioactive components silibinin and silychristine when administrated alone or in combination with DXR in the human prostate cancer cells (PC-3). PC-3 cells were treated with SEE, silibinin (silybins A and B), silychristine, alone, and in combination with DXR, and cell proliferation was assessed by the MTT assay. Cell cycle, apoptosis, and autophagy rate were assessed by flow cytometry. Expression levels of autophagy-related genes were quantified by qRT-PCR, ELISA and western blot while transmission electron microscopy was performed to reveal autophagic structures. Finally, NMR spectrometry was used to identify specific metabolites related to autophagy. SEE inhibited PC-3 cell proliferation in a dose-dependent manner while the co-treatment (DXR-SEE) revealed an additive cytotoxic effect. Cell cycle, apoptosis, and autophagy variations were observed in addition to altered expression levels of autophagy related genes (LC3, p62, NBR1, Beclin1, ULK1, AMBRA1), while several modifications in autophagic structures were identified after DXR-SEE co-treatment. Furthermore, treated cells showed a different metabolic profile, with significant alterations in autophagy-related metabolites such as branched-chain amino acids. In conclusion, the DXR-SEE co-treatment provokes perturbations in the autophagic mechanism of prostate cancer cells (PC-3) compared to DXR treatment alone, causing an excessive cell death. These findings propose the putative use of SEE as an adjuvant cytotoxic agent.

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Platelet-derived extracellular vesicles regulate cell cycle progression and cell migration in breast cancer cells

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/j.bbamcr.2020.118886 ◽

2021 ◽

Vol 1868 (1) ◽

pp. 118886

Author(s):

Mauro Vismara ◽

Marta Zarà ◽

Sharon Negri ◽

Jessica Canino ◽

Ilaria Canobbio ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Migration ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Breast Cancer Cells ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Regulate Cell Cycle Progression

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miR-3613 Regulates Gastric Cancer Cells Proliferation, Invasion, Migration and Apoptosis by Targeting Suppressor of Cytokine Signaling 4

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2019.22051699 ◽

2019 ◽

Vol 9 (12) ◽

pp. 1699-1705

Author(s):

Yuming Luo ◽

Wei Cao

Keyword(s):

Gastric Cancer ◽

Cell Cycle ◽

Western Blot ◽

Cancer Cells ◽

Cancer Cell ◽

Gastric Cancer Cell ◽

Target Genes ◽

Luciferase Reporter ◽

Gastric Cancer Cells ◽

And Migration

The present study aimed to investigate the effect of miR-3613 on the biological functions of gastric cancer cell lines. The expression of miR-3613 and SOCS4 in gastric cancer cells were detected by RT-qPCR and western blot. The target genes of miR-3613 were verified with the luciferase reporter system and western blot. The SOCS4 overexpression plasmid was constructed and transfected into gastric cancer cells. To further investigate the function of miR-3613, shRNA targeting miR-3613 and SOCS4 overexpression were transfected into SGC-7901. The growth of cells was detected by CCK-8, then the cell invasion and migration ability were detected by wound healing and transwell. Furthermore, the level of cell cycle was detected by flow cytometry. The expression of cell proliferation, cyclin and migration-related proteins were detected by western blot. The results revealed that the expression of miR-3613 is significantly increased in gastric cancer cells. SOCS4 is one of the target genes of miR-3613. Additionally, interference with miR-3613 promotes cell cycle arrest in gastric cancer cells and reversed the inhibitory effect of miR-3613 on biological function of gastric cells. Collectively, the data demonstrated that miR-3613 regulates gastric cancer cell by targeting SOCS4, which is expected to be an attractive target for the development of new drugs for the treatment of gastric cancer.

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Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells

Molecular Biology of the Cell ◽

10.1091/mbc.e14-12-1634 ◽

2015 ◽

Vol 26 (11) ◽

pp. 1971-1984 ◽

Cited By ~ 24

Author(s):

Julia Lindqvist ◽

Susumu Y. Imanishi ◽

Elin Torvaldson ◽

Marjo Malinen ◽

Mika Remes ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Androgen Receptor ◽

Cancer Cells ◽

Target Genes ◽

Growth Promotion ◽

Intracellular Localization ◽

Prostate Cancer Cells ◽

Promoting Effect ◽

Akt Activation

Contrary to cell cycle–associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in differentiated cells and its destructive activation in Alzheimer's disease. Recently, CDK5 has been implicated in a number of different cancers, but how it is able to stimulate cancer-related signaling pathways remains enigmatic. Our goal was to study the cancer-promoting mechanisms of CDK5 in prostate cancer. We observed that CDK5 is necessary for proliferation of several prostate cancer cell lines. Correspondingly, there was considerable growth promotion when CDK5 was overexpressed. When examining the reasons for the altered proliferation effects, we observed that CDK5 phosphorylates S308 on the androgen receptor (AR), resulting in its stabilization and differential expression of AR target genes including several growth-priming transcription factors. However, the amplified cell growth was found to be separated from AR signaling, further corroborated by CDK5-depdent proliferation of AR null cells. Instead, we found that the key growth-promoting effect was due to specific CDK5-mediated AKT activation. Down-regulation of CDK5 repressed AKT phosphorylation by altering its intracellular localization, immediately followed by prominent cell cycle inhibition. Taken together, these results suggest that CDK5 acts as a crucial signaling hub in prostate cancer cells by controlling androgen responses through AR, maintaining and accelerating cell proliferation through AKT activation, and releasing cell cycle breaks.

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