scholarly journals Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation

2021 ◽  
Vol 11 ◽  
Author(s):  
Ziyi Zhao ◽  
Jinhao Zeng ◽  
Qiang Guo ◽  
Kunming Pu ◽  
Yi Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Isoquinoline Alkaloid ◽  
Negative Regulator ◽  
Cancer Therapies ◽  
Antitumor Activities ◽  
Chemotherapy Agent ◽  
Cycle Arrest ◽  
After Cancer ◽  
Induced Apoptosis

BackgroundCancer stem cells (CSCs) are able to survive after cancer therapies, resulting in tumor progression and recurrence, as is seen in colorectal cancer. Therapies targeting CSCs are regarded as novel and promising strategies for efficiently eradicating tumors. Berberine, an isoquinoline alkaloid extracted from the Chinese herbal medicine Coptis chinensis, was found to have antitumor activities against colorectal cancer, without knowing whether it exerts inhibitory effects on colorectal CSCs and the potential mechanisms.MethodsIn this study, we examined the inhibitory roles of Berberine on CSCs derived from HCT116 and HT29 by culturing in serum-free medium. We also examined the effects of Berberine on m6A methylation via regulating fat mass and obesity-associated protein (FTO), by downregulating β-catenin.ResultsWe examined the effects of Berberine on the tumorigenicity, growth, and stemness of colorectal cancer stem-like cells. The regulatory effect of Berberine on N6-methyladenosine (m6A), an abundant mRNA modification, was also examined. Berberine treatment decreased cell proliferation by decreasing cyclin D1 and increasing p27 and p21 and subsequently induced cell cycle arrest at the G1/G0 phase. Berberine treatment also decreased colony formation and induced apoptosis. Berberine treatment transcriptionally increased FTO and thus decreased m6A methylation, which was reversed by both FTO knockdown and the addition of the FTO inhibitor FB23-2. Berberine induced FTO-related decreases in stemness in HCT116 and HT29 CSCs. Berberine treatment also increased chemosensitivity in CSCs and promoted chemotherapy agent-induced apoptosis. Moreover, we also found that Berberine treatment increased FTO by decreasing β-catenin, which is a negative regulator of FTO.ConclusionsOur observation that Berberine effectively decreased m6A methylation by decreasing β-catenin and subsequently increased FTO suggests a role of Berberine in modulating stemness and malignant behaviors in colorectal CSCs.

Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies

2020 ◽  
Vol 15 (6) ◽  
pp. 482-491 ◽  
Author(s):  
Milena Kostadinova ◽  
Milena Mourdjeva
Keyword(s):  
Cancer Cells ◽  
Small Population ◽  
Tumor Formation ◽  
Bioactive Molecules ◽  
Cancer Therapies ◽  
New Methods ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Blocking Mechanisms

Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.

scholarly journals Roles of pRB in the Regulation of Nucleosome and Chromatin Structures

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Chiharu Uchida
Keyword(s):  
Target Genes ◽  
Chromosome Instability ◽  
Cancer Therapies ◽  
Induce Cell Cycle Arrest ◽  
Cellular Events ◽  
Cycle Arrest ◽  
Histone Modifiers ◽  
Physical Interactions ◽  
Functional Inactivation

Retinoblastoma protein (pRB) interacts with E2F and other protein factors to play a pivotal role in regulating the expression of target genes that induce cell cycle arrest, apoptosis, and differentiation. pRB controls the local promoter activity and has the ability to change the structure of nucleosomes and/or chromosomes via histone modification, epigenetic changes, chromatin remodeling, and chromosome organization. Functional inactivation of pRB perturbs these cellular events and causes dysregulated cell growth and chromosome instability, which are hallmarks of cancer cells. The role of pRB in regulation of nucleosome/chromatin structures has been shown to link to tumor suppression. This review focuses on the ability of pRB to control nucleosome/chromatin structures via physical interactions with histone modifiers and chromatin factors and describes cancer therapies based on targeting these protein factors.

scholarly journals Update on the role of pembrolizumab in patients with unresectable or metastatic colorectal cancer

2021 ◽  
Vol 14 ◽  
pp. 175628482110244
Author(s):  
Vanessa Wookey ◽  
Axel Grothey
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Cancer Type ◽  
Cancer Therapies ◽  
Multiple Cancer ◽  
Multiple Treatment

Colorectal cancer (CRC) is the third most common cancer type in both men and women in the USA. Most patients with CRC are diagnosed as local or regional disease. However, the survival rate for those diagnosed with metastatic disease remains disappointing, despite multiple treatment options. Cancer therapies for patients with unresectable or metastatic CRC are increasingly being driven by particular biomarkers. The development of various immune checkpoint inhibitors has revolutionized cancer therapy over the last decade by harnessing the immune system in the treatment of cancer, and the role of immunotherapy continues to expand and evolve. Pembrolizumab is an anti-programmed cell death protein 1 immune checkpoint inhibitor and has become an essential part of the standard of care in the treatment regimens for multiple cancer types. This paper reviews the increasing evidence supporting and defining the role of pembrolizumab in the treatment of patients with unresectable or metastatic CRC.

scholarly journals The essential role of TAp73 in bortezomib-induced apoptosis in p53-deficient colorectal cancer cells

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Yasamin Dabiri ◽  
Sara Kalman ◽  
Clara-Marie Gürth ◽  
Jee Young Kim ◽  
Viola Mayer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Essential Role ◽  
Colorectal Cancer Cells ◽  
Induced Apoptosis

scholarly journals The p53/miR-34a/SIRT1 Positive Feedback Loop in Quercetin-Induced Apoptosis

2015 ◽  
Vol 35 (6) ◽  
pp. 2192-2202 ◽  
Author(s):  
Guohua Lou ◽  
Yanning Liu ◽  
Shanshan Wu ◽  
Jihua Xue ◽  
Fan Yang ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Rt Pcr ◽  
Cycle Arrest ◽  
Anticancer Effects ◽  
Huh7 Cells ◽  
Mirnas Expression ◽  
Induced Apoptosis

Background: The anti-tumor effects of quercetin have been reported, but the underlying molecular mechanisms remain to be elucidated. The aim of present study was to explore the role of miRNA in the anticancer effects of quercetin. Methods: The differential miRNAs expression between the HepG2 and Huh7 cells treated by quercetin were detected by microarray. The xCELLigence, Flow cytometry, RT-PCR and Western blot were used to analyze the cell proliferation, cell apoptosis, cell cycle arrest, anti-tumor genes, and protein expression. Results: miR-34a was up-regulated in HepG2 cells treated by quercetin exhibiting wild-type p53. When inhibiting the miR-34a, the sensitivity of the cells to quercetin decreased and the expression of the SIRT1 was up-regulated, but the acetylation of p53 and the expression of some genes related to p53 down-regulated. Conclusion: miR-34a plays an important role in the anti-tumor effects of querctin in HCC, miR-34a may be a tiemolecule between the p53 and SIRT1 and is composed of a p53/miR-34a/SIRT1 signal feedback loop, which could enhance apoptosis signal and significantly promote cell apoptosis.

scholarly journals MicroRNAs and Apoptosis in Colorectal Cancer

2020 ◽  
Vol 21 (15) ◽  
pp. 5353 ◽  
Author(s):  
Hsiuying Wang
Keyword(s):  
Colorectal Cancer ◽  
Treatment Resistance ◽  
Therapeutic Resistance ◽  
Cancer Therapies ◽  
Malignant Cells ◽  
Apoptosis Induction ◽  
The Third ◽  
Anti Cancer ◽  
The World

Colorectal cancer (CRC) is the third leading cause of cancer death in the world, and its incidence is rising in developing countries. Treatment with 5-Fluorouracil (5-FU) is known to improve survival in CRC patients. Most anti-cancer therapies trigger apoptosis induction to eliminate malignant cells. However, de-regulated apoptotic signaling allows cancer cells to escape this signaling, leading to therapeutic resistance. Treatment resistance is a major challenge in the development of effective therapies. The microRNAs (miRNAs) play important roles in CRC treatment resistance and CRC progression and apoptosis. This review discusses the role of miRNAs in contributing to the promotion or inhibition of apoptosis in CRC and the role of miRNAs in modulating treatment resistance in CRC cells.

scholarly journals Role of Cdc42-Cla4 Interaction in the Pheromone Response of Saccharomyces cerevisiae

2006 ◽  
Vol 6 (2) ◽  
pp. 317-327 ◽  
Author(s):  
Melanie Heinrich ◽  
Tim Köhler ◽  
Hans-Ulrich Mösch
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Map Kinase ◽  
Cell Cycle Arrest ◽  
Map Kinases ◽  
Negative Regulator ◽  
Cycle Arrest ◽  
Mitogen Activated Protein ◽  
Novel Alleles

ABSTRACT In Saccharomyces cerevisiae, the highly conserved Rho-type GTPase Cdc42 is essential for cell division and controls cellular development during mating and invasive growth. The role of Cdc42 in mating has been controversial, but a number of previous studies suggest that the GTPase controls the mitogen-activated protein (MAP) kinase cascade by activating the p21-activated protein kinase (PAK) Ste20. To further explore the role of Cdc42 in pheromone-stimulated signaling, we isolated novel alleles of CDC42 that confer resistance to pheromone. We find that in CDC42(V36A) and CDC42(V36A, I182T) mutant strains, the inability to undergo pheromone-induced cell cycle arrest correlates with reduced phosphorylation of the mating MAP kinases Fus3 and Kss1 and with a decrease in mating efficiency. Furthermore, Cdc42(V36A) and Cdc42(V36A, I182T) proteins show reduced interaction with the PAK Cla4 but not with Ste20. We also show that deletion of CLA4 in a CDC42(V36A, I182T) mutant strain suppresses pheromone resistance and that overexpression of CLA4 interferes with pheromone-induced cell cycle arrest and MAP kinase phosphorylation in CDC42 wild-type strains. Our data indicate that Cla4 has the potential to act as a negative regulator of the mating pathway and that this function of the PAK might be under control of Cdc42. In conclusion, our study suggests that control of pheromone signaling by Cdc42 not only depends on Ste20 but also involves interaction of the GTPase with Cla4.

scholarly journals The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration

2011 ◽  
Vol 22 (17) ◽  
pp. 3032-3040 ◽  
Author(s):  
Aichi Msaki ◽  
Ana M. Sánchez ◽  
Li Fang Koh ◽  
Benjamin Barré ◽  
Sonia Rocha ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Cellular Migration ◽  
Negative Regulator ◽  
Drug Induced ◽  
Conserved Residues ◽  
Cellular Processes ◽  
And Migration ◽  
Induced Apoptosis ◽  
Proliferation And Migration

The NF-κB family of transcription factors is a well-established regulator of the immune and inflammatory responses and also plays a key role in other cellular processes, including cell death, proliferation, and migration. Conserved residues in the trans-activation domain of RelA, which can be posttranslationally modified, regulate divergent NF-κB functions in response to different cellular stimuli. Using rela−/−mouse embryonic fibroblasts reconstituted with RelA, we find that mutation of the threonine 505 (T505) phospho site to alanine has wide-ranging effects on NF-κB function. These include previously described effects on chemotherapeutic drug-induced apoptosis, as well as new roles for this modification in autophagy, cell proliferation, and migration. This last effect was associated with alterations in the actin cytoskeleton and expression of cellular migration–associated genes such as WAVE3 and α-actinin 4. We also define a new component of cisplatin-induced, RelA T505–dependent apoptosis, involving induction of NOXA gene expression, an effect explained at least in part through induction of the p53 homologue, p73. Therefore, in contrast to other RelA phosphorylation events, which positively regulate NF-κB function, we identified RelA T505 phosphorylation as a negative regulator of its ability to induce diverse cellular processes such as apoptosis, autophagy, proliferation, and migration.

scholarly journals VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3512
Author(s):  
Sofiane Berrazouane ◽  
Alexie Doucet ◽  
Marc Boisvert ◽  
Frédéric Barabé ◽  
Fawzi Aoudjit
Keyword(s):  
Cell Adhesion ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Cancer Therapies ◽  
Anti Cancer ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Stromal Cell Derived Factor ◽  
Induced Apoptosis ◽  
Inhibition Studies

Cell adhesion plays a critical role in the development of chemoresistance, which is a major issue in anti-cancer therapies. In this study, we have examined the role of the VLA-4 integrin, a major adhesion molecule of the immune system, in the chemoresistance of T-ALL cells. We found that attachment of Jurkat and HSB-2 T-ALL cells to VCAM-1, a VLA-4 ligand, inhibits doxorubicin-induced apoptosis. However, their adhesion to fibronectin, which is mainly mediated via VLA-5, had no effect. Even the presence of the chemoattractant SDF1α (Stromal cell-derived factor-1α), which enhances the adhesion of T-ALL cells to fibronectin, did not modify the sensitivity of the cells attached on fibronectin towards doxorubicin-induced apoptosis. Mechanistically, we found that VLA-4 promoted T-ALL chemoresistance by inducing doxorubicin efflux. Our results showed that cell adhesion to both fibronectin and VCAM-1-induced Focal adhesion kinase (FAK) phosphorylation in T-ALL cells. However, only cell adhesion to VCAM-1 led to PYK2 phosphorylation. Inhibition studies indicated that FAK is not involved in doxorubicin efflux and chemoresistance, whereas PYK2 inhibition abrogated both VLA-4-induced doxorubicin efflux and chemoresistance. Together, these results indicate that the VLA-4/PYK2 pathway could participate in T-ALL chemoresistance and its targeting could be beneficial to limit/avoid chemoresistance and patient relapse.

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