Exosome-transmitted miR-769-5p confers cisplatin resistance and tumorigenesis in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53

AbstractCisplatin resistance is the main cause of poor clinical prognosis in patients with gastric cancer (GC). Yet, the exact mechanism of cisplatin resistance remains unclear. Recent studies have suggested that exocrine miRNAs found in the tumor microenvironment participates in tumor metastasis and drug resistance. In this study, we discovered that cisplatin-resistant GC cells communicate with the tumor microenvironment by secreting microvesicles. The biologically active miR-769-5p can be integrated into exosomes and delivered to sensitive cells, thereby spreading cisplatin resistance. Mi769-5p was upregulated in GC tissues and enriched in the serum exosomes of cisplatin-resistant patients. Mechanistically, miR-769-5p promotes cisplatin resistance by targeting CASP9 so as to inhibit the downstream caspase pathway and promote the degradation of the apoptosis-related protein p53 through the ubiquitin-proteasome pathway. Targeting miR-769 with its antagonist to treat cisplatin-resistant GC cells can restore the cisplatin response, confirming that exosomal miR-769-5p can be a key regulator of cisplatin resistance in GC. Therefore, exosomal miR-769-5p derived from drug-resistant cells can be used as a potential therapeutic predictor of anti-tumor chemotherapy to enhance the effect of anti-cancer chemotherapy, which provides a new treatment option for GC.

Download Full-text

Kaempferol Modulates DNA Methylation and Downregulates DNMT3B in Bladder Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000464435 ◽

2017 ◽

Vol 41 (4) ◽

pp. 1325-1335 ◽

Cited By ~ 30

Author(s):

Wei Qiu ◽

Jun Lin ◽

Yichen Zhu ◽

Jian Zhang ◽

Liping Zeng ◽

...

Keyword(s):

Dna Methylation ◽

Bladder Cancer ◽

Genomic Dna ◽

Fruits And Vegetables ◽

Dna Methyltransferases ◽

Protein Levels ◽

Anti Cancer ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Illumina Infinium Humanmethylation

Background: Genomic DNA methylation plays an important role in both the occurrence and development of bladder cancer. Kaempferol (Kae), a natural flavonoid that is present in many fruits and vegetables, exhibits potent anti-cancer effects in bladder cancer. Similar to other flavonoids, Kae possesses a flavan nucleus in its structure. This structure was reported to inhibit DNA methylation by suppressing DNA methyltransferases (DNMTs). However, whether Kae can inhibit DNA methylation remains unclear. Methods: Nude mice bearing bladder cancer were treated with Kae for 31 days. The genomic DNA was extracted from xenografts and the methylation changes was determined using an Illumina Infinium HumanMethylation 450 BeadChip Array. The ubiquitination was detected using immuno-precipitation assay. Results: Our data indicated that Kae modulated DNA methylation in bladder cancer, inducing 103 differential DNA methylation positions (dDMPs) associated with genes (50 hyper-methylated and 53 hypo-methylated). DNA methylation is mostly relied on the levels of DNMTs. We observed that Kae specifically inhibited the protein levels of DNMT3B without altering the expression of DNMT1 or DNMT3A. However, Kae did not downregulate the transcription of DNMT3B. Interestingly, we observed that Kae induced a premature degradation of DNMT3B by inhibiting protein synthesis with cycloheximide (CHX). By blocking proteasome with MG132, we observed that Kae induced an increased ubiquitination of DNMT3B. These results suggested that Kae could induce the degradation of DNMT3B through ubiquitin-proteasome pathway. Conclusion: Our data indicated that Kae is a novel DNMT3B inhibitor, which may promote the degradation of DNMT3B in bladder cancer.

Download Full-text

Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance

Drug Resistance Updates ◽

10.1016/j.drup.2019.100663 ◽

2020 ◽

Vol 48 ◽

pp. 100663 ◽

Cited By ~ 16

Author(s):

Silpa Narayanan ◽

Chao-Yun Cai ◽

Yehuda G. Assaraf ◽

Hui-Qin Guo ◽

Qingbin Cui ◽

...

Keyword(s):

Drug Resistance ◽

Cancer Drug ◽

Ubiquitin Proteasome Pathway ◽

Cancer Drug Resistance ◽

Anti Cancer ◽

Ubiquitin Proteasome ◽

Proteasome Pathway

Download Full-text

APC/C and retinoblastoma interaction: cross-talk of retinoblastoma protein with the ubiquitin proteasome pathway

Bioscience Reports ◽

10.1042/bsr20160152 ◽

2016 ◽

Vol 36 (5) ◽

Cited By ~ 5

Author(s):

Ajeena Ramanujan ◽

Swati Tiwari

Keyword(s):

Cell Cycle ◽

Cell Cycle Regulation ◽

Alternative Pathway ◽

Retinoblastoma Protein ◽

S Phase ◽

Anaphase Promoting Complex ◽

Anti Cancer ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Cycle Regulation

The ubiquitin (Ub) ligase anaphase promoting complex/cyclosome (APC/C) and the tumour suppressor retinoblastoma protein (pRB) play key roles in cell cycle regulation. APC/C is a critical regulator of mitosis and G1-phase of the cell cycle whereas pRB keeps a check on proliferation by inhibiting transition to the S-phase. APC/C and pRB interact with each other via the co-activator of APC/C, FZR1, providing an alternative pathway of regulation of G1 to S transition by pRB using a post-translational mechanism. Both pRB and FZR1 have complex roles and are implicated not only in regulation of cell proliferation but also in differentiation, quiescence, apoptosis, maintenance of chromosomal integrity and metabolism. Both are also targeted by transforming viruses. We discuss recent advances in our understanding of the involvement of APC/C and pRB in cell cycle based decisions and how these insights will be useful for development of anti-cancer and anti-viral drugs.

Download Full-text

Binding Performance of Human Intravenous Immunoglobulin and 20(S)-7-Ethylcamptothecin

Molecules ◽

10.3390/molecules23092389 ◽

2018 ◽

Vol 23 (9) ◽

pp. 2389

Author(s):

Yong-Chun Liu ◽

Ying-Ying Li ◽

Xiao-Jun Yao ◽

Hui-Li Qi ◽

Xiao-Xia Wei ◽

...

Keyword(s):

Intravenous Immunoglobulin ◽

Binding Mode ◽

Biologically Active ◽

Treatment Protocols ◽

Transporter Protein ◽

Spontaneous Interaction ◽

Anti Cancer ◽

Binding Cavity ◽

New Treatment

A previous study showed that intravenous immunoglobulin (IVIG) could preserve higher levels of biologically active lactone moieties of topotecan, 7-ethyl-10-hydroxycamptothecin (SN-38) and 10-hydroxycamptothecin at physiological pH 7.40. As one of camptothecin analogues (CPTs), the interaction of 7-ethylcamptothecin and IVIG was studied in vitro in this study. It was shown that the main binding mode of IVIG to 7-ethylcamptothecin was hydrophobic interaction and hydrogen bonding, which is a non-specific and spontaneous interaction. The hydrophobic antigen-binding cavity of IgG would enwrap the drug into a host-guest inclusion complex and prevent hydrolysis of the encapsulated drug, while the drug is adjacent to the chromophores of IgG and may exchange energy with chromophores and quench the fluorescence of the protein. Also, the typical β-sheet structure of IVIG unfolded partially after binding to 7-ethylcamptothecin. Additionally, the binding properties of IVIG and six CPTs with different substituents at A-ring and/or B-ring including camptothecin, topotecan, irinotecan, 10-hydroxycamptothecin, 7-ethylcamptothecin and SN-38 were collected together and compared each other. Synergizing with anti-cancer drugs, IVIG could be used as a transporter protein for 7-ethylcamptothecin and other CPTs, allowing clinicians to devise new treatment protocols for patients.

Download Full-text

IRTKS is correlated with progression and survival time of patients with gastric cancer

Gut ◽

10.1136/gutjnl-2016-313478 ◽

2017 ◽

Vol 67 (8) ◽

pp. 1400-1409 ◽

Cited By ~ 10

Author(s):

Li-Yu Huang ◽

Xuefei Wang ◽

Xiao-Fang Cui ◽

He Li ◽

Junjie Zhao ◽

...

Keyword(s):

Gastric Cancer ◽

Survival Time ◽

Target Genes ◽

Human Gastric Cancer ◽

Wild Type ◽

Gastric Cancer Cells ◽

Ubiquitin Proteasome ◽

Proteasome Pathway

Background and objectivesIRTKS functions as a novel regulator of tumour suppressor p53; however, the role of IRTKS in pathogenesis of gastric cancer is unclear.DesignWe used immunohistochemistry to detect IRTKS levels in 527 human gastric cancer specimens. We generated both IRTKS-deficient and p53-deficient mice to observe survival time of these mice and to isolate mouse embryonic fibroblasts (MEFs) for evaluating in vivo tumorigenicity. Co-immunoprecipitation was used to study the interaction among p53, MDM2 and IRTKS, as well as the ubiquitination of p53.ResultsIRTKS was significantly overexpressed in human gastric cancer, which was conversely associated with wild-type p53 expression. Among patients with wild-type p53 (n=206), those with high IRTKS expression (n=141) had a shorter survival time than those with low IRTKS (n=65) (p=0.0153). Heterozygous p53+/− mice with IRTKS deficiency exhibited significantly delayed tumorigenesis and an extended tumour-free survival time. p53+/− MEFs without IRTKS exhibited attenuated in vivo tumorigenicity. IRTKS depletion upregulated p53 and its target genes, such as BAX and p21. Intriguingly, IRTKS overexpression promoted p53 ubiquitination and degradation in MEFs and gastric cancer cells. Under DNA damage conditions, IRTKS was phosphorylated at Ser331 by the activated Chk2 kinase and then dissociated from p53, along with the p53-specific E3 ubiquitin ligase MDM2, resulting in attenuated p53 ubiquitination and degradation.ConclusionIRTKS overexpression is negatively correlated with progression and overall survival time of patients with gastric cancer with wild-type p53 through promotion of p53 degradation via the ubiquitin/proteasome pathway.

Download Full-text

The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites

Parasitology ◽

10.1017/s003118200500747x ◽

2005 ◽

Vol 131 (1) ◽

pp. 37-44 ◽

Cited By ~ 55

Author(s):

C. LINDENTHAL ◽

N. WEICH ◽

Y.-S. CHIA ◽

V. HEUSSLER ◽

M.-Q. KLINKERT

Keyword(s):

Protein Degradation ◽

Proteasome Inhibitor ◽

Proteasome Inhibitors ◽

Protein Conjugates ◽

Anti Cancer ◽

Dividing Cells ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Further Development ◽

Specific Peptide

Protein degradation is regulated during the cell cycle of all eukaryotic cells and is mediated by the ubiquitin-proteasome pathway. Potent and specific peptide-derived inhibitors of the 20S proteasome have been developed recently as anti-cancer agents, based on their ability to induce apoptosis in rapidly dividing cells. Here, we tested a novel small molecule dipeptidyl boronic acid proteasome inhibitor, named MLN-273 on blood and liver stages of Plasmodium species, both of which undergo active replication, probably requiring extensive proteasome activity. The inhibitor blocked Plasmodium falciparum erythrocytic development at an early ring stage as well as P. berghei exoerythrocytic progression to schizonts. Importantly, neither uninfected erythrocytes nor hepatocytes were affected by the drug. MLN-273 caused an overall reduction in protein degradation in P. falciparum, as demonstrated by immunoblots using anti-ubiquitin antibodies to label ubiquitin-tagged protein conjugates. This led us to conclude that the target of the drug was the parasite proteasome. The fact that proteasome inhibitors are presently used as anti-cancer drugs in humans forms a solid basis for further development and makes them potentially attractive drugs also for malaria chemotherapy.

Download Full-text

Proteasome inhibitors as therapeutics

Essays in Biochemistry ◽

10.1042/bse0410205 ◽

2005 ◽

Vol 41 ◽

pp. 205-218

Author(s):

Constantine S. Mitsiades ◽

Nicholas Mitsiades ◽

Teru Hideshima ◽

Paul G. Richardson ◽

Kenneth C. Anderson

Keyword(s):

Multiple Myeloma ◽

Drug Class ◽

Proteasome Inhibitors ◽

Cell Cycle Regulators ◽

Current State ◽

Intracellular Mechanism ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Hodgkin's Lymphomas ◽

Clinical Research Data

The ubiquitin–proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.

Download Full-text

Role of molecular chaperones in steroid receptor action

Essays in Biochemistry ◽

10.1042/bse0400041 ◽

2004 ◽

Vol 40 ◽

pp. 41-58 ◽

Cited By ~ 149

Author(s):

William B Pratt ◽

Mario D Galigniana ◽

Yoshihiro Morishima ◽

Patrick J M Murphy

Keyword(s):

Transcriptional Activation ◽

Protein Trafficking ◽

Steroid Receptors ◽

Transcriptional Regulatory ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Receptor Action ◽

Binding Cleft ◽

Hsp 90

Unliganded steroid receptors are assembled into heterocomplexes with heat-shock protein (hsp) 90 by a multiprotein chaperone machinery. In addition to binding the receptors at the chaperone site, hsp90 binds cofactors at other sites that are part of the assembly machinery, as well as immunophilins that connect the assembled receptor-hsp90 heterocomplexes to a protein trafficking pathway. The hsp90-/hsp70-based chaperone machinery interacts with the unliganded glucocorticoid receptor to open the steroid-binding cleft to access by a steroid, and the machinery interacts in very dynamic fashion with the liganded, transformed receptor to facilitate its translocation along microtubular highways to the nucleus. In the nucleus, the chaperone machinery interacts with the receptor in transcriptional regulatory complexes after hormone dissociation to release the receptor and terminate transcriptional activation. By forming heterocomplexes with hsp90, the chaperone machinery stabilizes the receptor to degradation by the ubiquitin-proteasome pathway of proteolysis.

Download Full-text