scholarly journals Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer

2012 ◽  
Vol 17 (3) ◽  
Author(s):  
Eva Ruckova ◽  
Petr Muller ◽  
Rudolf Nenutil ◽  
Borivoj Vojtesek
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Binding Sites ◽  
Patient Survival ◽  
Proliferating Cells ◽  
Response Elements ◽  
Over Expression ◽  
Hsp90 Activity ◽  
Hsp90 Chaperone ◽  
Client Proteins

AbstractActivation of the Hsp90 chaperone system is a characteristic of cancer cells. The regulation of chaperone activities involves their interaction with cochaperones; therefore we investigated the expression of Hsp70 and Hsp90 and their specific co-chaperones HOP and CHIP in cancer cell lines and primary cancers. Inhibition of Hsp90 by 17AAG increased the levels of Hsp70, Hsp90 and HOP but not CHIP mRNA in cancer cells. These changes are linked to activation of the HSF1 transcription factor and we show that the HOP promoter contains HSF1 binding sites, and that HSF1 binding to the HOP promoter is increased following 17AAG. The lack of alteration in the co-chaperone CHIP is explained by a lack of HSF response elements in the CHIP promoter. Non-proliferating cells expressed higher levels of CHIP and lower HOP, Hsp70 and Hsp90 levels compared to proliferating cells. Decreased expression of CHIP in proliferating cancer cells is in keeping with its proposed tumor suppressor properties, while over-expression of HOP in proliferating cells may contribute to excessive Hsp90 activity and stabilization of client proteins in tumors. In a panel of colorectal cancer samples, increased expression of Hsp70 and an increased ratio of HOP to CHIP were found, and were associated with decreased median survival. These data indicate that multiple changes occur in the chaperone/co-chaperone system in cancer that impact patient survival. It is likely that the ability to identify individual alterations to this system will be beneficial for treatment strategy decisions, particularly those that employ chaperone inhibitors.

scholarly journals Immuno-genomic classification of colorectal cancer organoids reveals cancer cells with intrinsic immunogenic properties associated with patient survival

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Eun Jeong Cho ◽  
Minsuh Kim ◽  
Daum Jo ◽  
Jihye Kim ◽  
Ji-Hye Oh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Patient Survival ◽  
Expression Profiles ◽  
Disease Stage ◽  
Large Set ◽  
Primary Tumors ◽  
Variable Expression ◽  
Immunogenic Properties

Abstract Background The intrinsic immuno-ge7nomic characteristics of colorectal cancer cells that affect tumor biology and shape the tumor immune microenvironment (TIM) are unclear. Methods We developed a patient-derived colorectal cancer organoid (CCO) model and performed pairwise analysis of 87 CCOs and their matched primary tumors. The TIM type of the primary tumor was classified as immuno-active, immuno-exhausted, or immuno-desert. Results The gene expression profiles, signaling pathways, major oncogenic mutations, and histology of the CCOs recapitulated those of the primary tumors, but not the TIM of primary tumors. Two distinct intrinsic molecular subgroups of highly proliferative and mesenchymal phenotypes with clinical significance were identified in CCOs with various cancer signaling pathways. CCOs showed variable expression of cancer-specific immune-related genes such as those encoding HLA-I and HLA-II, and molecules involved in immune checkpoint activation/inhibition. Among these genes, the expression of HLA-II in CCOs was associated with favorable patient survival. K-means clustering analysis based on HLA-II expression in CCOs revealed a subgroup of patients, in whom cancer cells exhibited Intrinsically Immunogenic Properties (Ca-IIP), and were characterized by high expression of signatures associated with HLA-I, HLA-II, antigen presentation, and immune stimulation. Patients with the Ca-IIP phenotype had an excellent prognosis, irrespective of age, disease stage, intrinsic molecular type, or TIM status. Ca-IIP was negatively correlated with intrinsic E2F/MYC signaling. Analysis of the correlation between CCO immuno-genotype and TIM phenotype revealed that the TIM phenotype was associated with microsatellite instability, Wnt/β-catenin signaling, APC/KRAS mutations, and the unfolded protein response pathway linked to the FBXW7 mutation in cancer cells. However, Ca-IIP was not associated with the TIM phenotype. Conclusions We identified a Ca-IIP phenotype from a large set of CCOs. Our findings may provide an unprecedented opportunity to develop new strategies for optimal patient stratification in this era of immunotherapy.

scholarly journals Lectin ZG16p inhibits proliferation of human colorectal cancer cells via its carbohydrate-binding sites

Glycobiology ◽  
2017 ◽  
Vol 28 (1) ◽  
pp. 21-31 ◽  
Author(s):  
Akiko Mito ◽  
Yukiko Nakano ◽  
Takako Saitoh ◽  
Sabine S S Gouraud ◽  
Yoshiki Yamaguchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Binding Sites ◽  
Carbohydrate Binding ◽  
Human Colorectal Cancer ◽  
Colorectal Cancer Cells ◽  
Human Colorectal Cancer Cells

scholarly journals MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer

2021 ◽  
Author(s):  
ManSai Acón ◽  
Carsten Geiß ◽  
Jorge Torres-Calvo ◽  
Guillermo Oviedo ◽  
Jorge L Arias-Arias ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Dosage Compensation ◽  
Patient Survival ◽  
Gene Dosage ◽  
Negative Effects ◽  
Over Expression ◽  
Factor Interactions ◽  
Computational Platform ◽  
Omic Data

AbstractCancer complexity is consequence of genomic instability leading to aneuploidy. We hypothesize that dosage compensation of critical genes arise from systems-level properties for cancer cells to withstand the negative effects of aneuploidy. We developed a computational platform to identify a network of miRNAs and transcription factors interacting with candidate dosage-compensated genes using NCI-60 multi-omic data. We next constructed a mathematical model where the property of dosage compensation emerged for MYC and STAT3 and was dependent on the kinetic parameters of their feedback and feed-forward interactions with four miRNAs. We developed a genetic tug-of-war approach by overexpressing an exogenous MYC sequence to experimentally validate MYC dosage compensation circuits as demonstrated by the over-expression of the three microRNAs involved and the respective down-regulation of endogenous MYC. In addition, MYC overexpression or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity in MYC-amplified colon cancer cells. The study of TCGA breast cancer patient data indicated that MYC dosage compensation could lead to lower patient survival, highlighting the potential of targeting gene dosage compensation to prevent aneuploid cancer progression.(BioNetUCR, available here: https://cloud.prislab.org/s/gt2W2jfZQx3E3Jm).

scholarly journals Genome-wide mapping of DNA-binding sites identifies stemness-related genes as directly repressed targets of SNAIL1 in colorectal cancer cells

Oncogene ◽  
2019 ◽  
Vol 38 (40) ◽  
pp. 6647-6661 ◽  
Author(s):  
Sven Beyes ◽  
Geoffroy Andrieux ◽  
Monika Schrempp ◽  
David Aicher ◽  
Janna Wenzel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Binding ◽  
Cancer Cells ◽  
Binding Sites ◽  
Dna Binding Sites ◽  
Genome Wide ◽  
Colorectal Cancer Cells

Hsp90 Quaternary Structures and the Chaperone Cycle: Highly Flexible Dimeric and Oligomeric Structures and Their Regulation by Co-Chaperones

2018 ◽  
Vol 16 (1) ◽  
pp. 5-11
Author(s):  
Eléonore Lepvrier ◽  
Daniel Thomas ◽  
Cyrille Garnier
Keyword(s):  
Conformational Changes ◽  
Client Protein ◽  
Key Players ◽  
Hsp90 Activity ◽  
Hsp90 Chaperone ◽  
Client Proteins ◽  
Quaternary Structures ◽  
Chaperone Interactions ◽  
High Flexibility ◽  
Future Work

Proposed models of the function of Hsp90 are characterised by high flexibility of the dimeric state and conformational changes regulated by both nucleotide binding and hydrolysis, and by co-chaperone interactions. In addition to its dimeric state, Hsp90 self-associates upon particular stimuli. The Hsp90 dimer is the building block up to the hexamer that we named “cosy nest”, and the dodecamer results from the association of two hexamers. Oligomers exhibit chaperone activity, but their exact mechanism of action has not yet been determined. One of the best ways to elucidate how oligomers might operate is to study their interactions with co-chaperone proteins known to regulate the Hsp90 chaperone cycle, such as p23 and Aha1. In this review, we summarise recent results and conclude that Hsp90 oligomers are key players in the chaperone cycle. Crucible-shaped quaternary structures likely provide an ideal environment for client protein accommodation and folding, as is the case for other Hsp families. Confirmation of the involvement of Hsp90 oligomers in the chaperone cycle and a better understanding of their functionality will allow us to address some of the more enigmatic aspects of Hsp90 activity. Utilising this knowledge, future work will highlight how Hsp90 oligomers and co-chaperones cooperate to build the structures required to fold or refold numerous different client proteins.

scholarly journals Over-expression of 14-3-3σ in budding colorectal cancer cells modulates cell migration in the presence of tenascin-C

2007 ◽  
Author(s):  
Munenori Ide ◽  
Kana Saito ◽  
Soichi Tsutsumi ◽  
Kaori Tsuboi ◽  
Satoru Yamaguchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Over Expression ◽  
Tenascin C ◽  
Colorectal Cancer Cells

scholarly journals DUSP16 promotes cancer chemoresistance through regulation of mitochondria-mediated cell death

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Heng Boon Low ◽  
Zhen Lim Wong ◽  
Bangyuan Wu ◽  
Li Ren Kong ◽  
Chin Wen Png ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cell Death ◽  
Cancer Cells ◽  
Patient Survival ◽  
Chemotherapy Treatment ◽  
Dual Specificity ◽  
Cancer Chemoresistance ◽  
Resistance To Chemotherapy

AbstractDrug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.

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