Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition DOI Creative Commons
Tamara Isermann,

Kim Lucia Schneider,

Florian Wegwitz

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 26, 2024

ABSTRACT The stress-associated molecular chaperone system is an actionable target in cancer therapies. It ubiquitously upregulated tissues and enables tumorigenicity by stabilizing hundreds of oncoproteins disturbing the stoichiometry protein complexes. Most inhibitors key component heat-shock 90 (HSP90). However, although classical HSP90 are highly tumor-selective, they fail phase 3 clinical oncology trials. These failures at least partly due to interference with a negative feedback loop inhibition, known as response (HSR): inhibition there compensatory synthesis stress-inducible chaperones, mediated transcription factor 1 (HSF1). We recently identified that wildtype p53 (p53) actively reduces HSR repressing HSF1 via p21-CDK4/6-MAPK-HSF1 axis. Here we test hypothesis HSP90-based therapies simultaneous activation or direct cell cycle interrupts deleterious HSF1-HSR axis improves efficiency inhibitors. Indeed, find clinically relevant activator Idasanutlin suppresses activity inhibitor-based This combination synergistically viability accelerates death p53-proficient colorectal (CRC) cells, murine tumor-derived organoids patient-derived (PDOs). Mechanistically, upon therapy human CRC cells strongly upregulate p53-associated pathways, apoptosis, inflammatory immune pathways. Likewise, chemical AOM/DSS model mice, dual HSF1-HSP90 represses tumor growth remodels composition, yet displays only minor toxicities mice normal mucosa-derived organoids. Importantly, cyclin dependent kinases 4 6 (CDK4/6) under phenocopies synergistic repression cells. Even more important, p53-deficient (mutp53-harboring) CDK4/6 similarly growth. p53-mutated PDOs respond pathway thus, providing strategy independent status. In sum, activating (in cells) inhibiting (independent status) provide new options improve outcome enhance therapy.

Язык: Английский

Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT DOI Creative Commons

María E Bernabeu-Herrero,

Dilipkumar Patel,

Adrianna Bielowka

и другие.

Blood, Год журнала: 2024, Номер 143(22), С. 2314 - 2331

Опубликована: Март 8, 2024

For monogenic diseases caused by pathogenic loss-of-function DNA variants, attention focuses on dysregulated gene-specific pathways, usually considering molecular subtypes together within causal genes. To better understand phenotypic variability in hereditary hemorrhagic telangiectasia (HHT), we subcategorized variants ENG/endoglin, ACVRL1/ALK1, and SMAD4 if they generated premature termination codons (PTCs) subject to nonsense-mediated decay. In 3 patient cohorts, a PTC-based classification system explained some previously puzzling hemorrhage variability. blood outgrowth endothelial cells (BOECs) derived from patients with ACVRL1+/PTC, ENG+/PTC, SMAD4+/PTC genotypes, PTC-containing RNA transcripts persisted at low levels (8%-23% expected, varying between replicate cultures); genes differentially expressed Bonferroni P < .05 HHT+/PTC BOECs clustered significantly only generic protein terms (isopeptide-bond/ubiquitin-like conjugation) pulse-chase experiments detected subtle maturation differences but no evidence for PTC-truncated protein. displaying highest PTC persistence were discriminated unsupervised hierarchical clustering of near-invariant housekeeper genes, patterns compatible higher cellular stress >11% persistence. test directionality, used HeLa reporter detect induction activating transcription factor 4 (ATF4), which controls expression stress-adaptive showed that ENG Q436X not R93X directly induced ATF4. AlphaFold accurately modeled relevant domains, AlphaMissense suggesting readthrough substitutions would be benign other less rare nonsense more damaging Q436X. We conclude PTCs should distinguished transcript increase stressed cells, proteins mechanisms provide promising research avenues.

Язык: Английский

Процитировано

8
HSP90 multi-functionality in cancer DOI Creative Commons
Zarema Albakova

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Авг. 1, 2024

The 90-kDa heat shock proteins (HSP90s) are molecular chaperones essential for folding, unfolding, degradation and activity of a wide range client proteins. HSP90s their cognate co-chaperones subject to various post-translational modifications, functional consequences which not fully understood in cancer. Intracellular extracellular HSP90 family members (HSP90α, HSP90β, GRP94 TRAP1) promote cancer by sustaining hallmarks cancer, including cell death resistance, replicative immortality, tumor immunity, angiogenesis, invasion metastasis. Given the importance progression, inhibitors HSP90-based vaccines were developed treatment Further understanding functions may provide new opportunities novel therapeutic strategies

Язык: Английский

Процитировано

7
Pharmacological Regulation of Heat Shock Response via Aptamer–Antidote Couple DOI
Jaskirat Kaur, Ipsita Roy

ACS Chemical Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Май 19, 2025

Heat shock factor 1 (HSF1) orchestrates the cellular heat response (HSR) by binding to elements (HSEs) in promoters of genes encoding proteins (HSPs). In a nonstressed state, HSF1 exists dormant complex with HSP90 and other chaperones. Upon stress or upon inhibition HSP90, dissociates from activates expression HSPs mitigate protein misfolding aggregation. This study explores potential RNA aptamers selected against modulate activity, role Huntington's disease model characterized Selected disrupted HSP90-HSF1 interaction, enhancing HSEs. upregulated reduced aggregation Q74-huntingtin Neuro 2a cells improved cell survival. Designed antidote sequences could reverse effect on HSF1-HSE allowing for fine-tuning HSR. Chronic activation pathways is deleterious fitness. Our findings suggest that coupling an aptamer offers novel therapeutic strategy regulate proteostasis under conditions.

Язык: Английский

Процитировано

0
First dual inhibitors of human topoisomerase IIα and Hsp90 C-terminal domain inhibit the growth of Ewing sarcoma in vitro and in vivo DOI Creative Commons
Jaka Dernovšek, Dunja Urbančič, Živa Zajec

и другие.

Bioorganic Chemistry, Год журнала: 2024, Номер 153, С. 107850 - 107850

Опубликована: Окт. 1, 2024

Язык: Английский

Процитировано

1
Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition DOI Creative Commons
Tamara Isermann,

Kim Lucia Schneider,

Florian Wegwitz

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 26, 2024

ABSTRACT The stress-associated molecular chaperone system is an actionable target in cancer therapies. It ubiquitously upregulated tissues and enables tumorigenicity by stabilizing hundreds of oncoproteins disturbing the stoichiometry protein complexes. Most inhibitors key component heat-shock 90 (HSP90). However, although classical HSP90 are highly tumor-selective, they fail phase 3 clinical oncology trials. These failures at least partly due to interference with a negative feedback loop inhibition, known as response (HSR): inhibition there compensatory synthesis stress-inducible chaperones, mediated transcription factor 1 (HSF1). We recently identified that wildtype p53 (p53) actively reduces HSR repressing HSF1 via p21-CDK4/6-MAPK-HSF1 axis. Here we test hypothesis HSP90-based therapies simultaneous activation or direct cell cycle interrupts deleterious HSF1-HSR axis improves efficiency inhibitors. Indeed, find clinically relevant activator Idasanutlin suppresses activity inhibitor-based This combination synergistically viability accelerates death p53-proficient colorectal (CRC) cells, murine tumor-derived organoids patient-derived (PDOs). Mechanistically, upon therapy human CRC cells strongly upregulate p53-associated pathways, apoptosis, inflammatory immune pathways. Likewise, chemical AOM/DSS model mice, dual HSF1-HSP90 represses tumor growth remodels composition, yet displays only minor toxicities mice normal mucosa-derived organoids. Importantly, cyclin dependent kinases 4 6 (CDK4/6) under phenocopies synergistic repression cells. Even more important, p53-deficient (mutp53-harboring) CDK4/6 similarly growth. p53-mutated PDOs respond pathway thus, providing strategy independent status. In sum, activating (in cells) inhibiting (independent status) provide new options improve outcome enhance therapy.

Язык: Английский

Процитировано

0