DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: April 30, 2020

Abstract Radiotherapy is one of the most common countermeasures for treating a wide range tumors. However, radioresistance cancer cells still major limitation radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers improving outcomes radiotherapy. DNA double-strand breaks lethal lesions induced by ionizing radiation can trigger series cellular damage responses (DDRs), including those helping recover from injuries, such as activation sensing early transduction pathways, cell cycle arrest, repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy overcoming radioresistance, some important advances breakthroughs have already been achieved in recent years. On basis comprehensively reviewing signal we provide update on novel promising druggable emerging that be exploited radiosensitization. We further discuss identified preclinical studies, current clinical trials, application chemical inhibitors targeting key proteins, DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia–telangiectasia mutated Rad3-related), MRN (MRE11-RAD50-NBS1) complex, PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, HIF-1 (hypoxia-inducible factor-1). Challenges radiation-induced targeted therapy also discussed based achievements biological field

Language: Английский

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The antitumorigenic roles of BRCA1–BARD1 in DNA repair and replication

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 21(5), P. 284 - 299

Published: Feb. 24, 2020

Language: Английский

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Molecular, cellular and systemic aspects of epithelial ovarian cancer and its tumor microenvironment

Seminars in Cancer Biology, Journal Year: 2022, Volume and Issue: 86, P. 207 - 223

Published: April 5, 2022

Ovarian cancer encompasses a heterogeneous group of malignancies that involve the ovaries, fallopian tubes and peritoneal cavity. Despite major advances made within field cancer, majority patients with ovarian are still being diagnosed at an advanced stage disease due to lack effective screening tools. The overall survival these has, therefore, not substantially improved over past decades. Most undergo debulking surgery treatment chemotherapy, but often micrometastases remain acquire resistance therapy, eventually leading recurrence. Here, we summarize current knowledge in epithelial development metastatic progression. For most common subtypes, focus further on properties functions immunosuppressive tumor microenvironment, including extracellular matrix. Current future modalities discussed finally provide overview different experimental models used develop novel therapies.

Language: Английский

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Complexities of Prostate Cancer

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(22), P. 14257 - 14257

Published: Nov. 17, 2022

Prostate cancer has a long disease history and wide variety uncertainty in individual patients’ clinical progress. In recent years, we have seen revolutionary advance both prostate patient care the research field. The power of deep sequencing provided cistromic transcriptomic knowledge that not discovered before. Our understanding biology, from bedside molecular imaging techniques, also been greatly advanced. It is important our current theragnostic schemes, including diagnostic modalities, therapeutic responses, drugs available to target non-AR signaling should be improved. This review article discusses progress biology advances strategies.

Language: Английский

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Post-Translational Modifications of Proteins Orchestrate All Hallmarks of Cancer

Life, Journal Year: 2025, Volume and Issue: 15(1), P. 126 - 126

Published: Jan. 18, 2025

Post-translational modifications (PTMs) of proteins dynamically build the buffering and adapting interface between oncogenic mutations environmental stressors, on one hand, cancer cell structure, functioning, behavior. Aberrant PTMs can be considered as enabling characteristics long they orchestrate all malignant variability in proteome cells, cancer-associated tumor microenvironment (TME). On other enhance anticancer mechanisms tumoral ecosystem or sustain beneficial effects oncologic therapies through degradation inactivation carcinogenic or/and activation tumor-suppressor proteins. In this review, we summarized analyzed a wide spectrum involved regulatory that drive tumorigenesis, genetic instability, epigenetic reprogramming, events metastatic cascade, cytoskeleton extracellular matrix (ECM) remodeling, angiogenesis, immune response, tumor-associated microbiome, metabolism rewiring most important hallmarks cancer. All develop due to proteins, which modulate gene transcription, intracellular signaling, protein size, activity, stability localization, trafficking, secretion, half-life, protein–protein interactions (PPIs). associated with exploited better understand underlying molecular heterogeneous chameleonic disease, find new biomarkers progression prognosis, personalize oncotherapies, discover targets for drug development.

Language: Английский

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DNA Damage Response and Immune Defense

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(20), P. 7504 - 7504

Published: Oct. 12, 2020

DNA damage is the cause of numerous human pathologies including cancer, premature aging, and chronic inflammatory conditions. The response (DDR), in turn, coordinates checkpoint activation promotes removal lesions. In recent years, several studies have shown how DDR immune system are tightly connected, revealing an important crosstalk between two them. This interesting interplay has opened up new perspectives clinical for immunological diseases as well cancer treatment. this review, we provide overview, from cellular to molecular pathways, on communicate share crucial commitment maintaining genomic fitness.

Language: Английский

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Overcoming PARPi resistance: Preclinical and clinical evidence in ovarian cancer

Drug Resistance Updates, Journal Year: 2021, Volume and Issue: 55, P. 100744 - 100744

Published: Jan. 18, 2021

Language: Английский

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Cancer as a prospective sequela of long COVID‐19

BioEssays, Journal Year: 2021, Volume and Issue: 43(6)

Published: April 29, 2021

Abstract As the spread of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) continues to surge worldwide, our knowledge disease 2019 (COVID‐19) is rapidly expanding. Although most COVID‐19 patients recover within weeks symptom onset, some experience lingering symptoms that last for months (“long COVID‐19”). Early reports sequelae, including cardiovascular, pulmonary, and neurological conditions, have raised concerns about long‐term effects COVID‐19, especially in hard‐hit communities. It becoming increasingly evident cancer are more susceptible SARS‐CoV‐2 infection at a higher risk than general population. Nevertheless, whether long increases those with no prior malignancies, remains unclear. Given, disproportionate impact on African American community, yet another unanswered question racial disparities be expected sequelae. Herein, we propose may predispose recovered development accelerate progression. This hypothesis based growing evidence ability modulate oncogenic pathways, promote chronic low‐grade inflammation, cause tissue damage. Comprehensive studies urgently required elucidate susceptibility.

Language: Английский

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Hereditary Pancreatic Cancer: Advances in Genetic Testing, Early Detection Strategies, and Personalized Management

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(2), P. 367 - 367

Published: Jan. 9, 2025

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with five-year survival rate of approximately 13% for advanced stages. While the majority PDAC cases are sporadic, significant subset attributable to hereditary and familial predispositions, accounting 25% cases. This article synthesizes recent advancements in understanding, detection, management pancreatic cancer (PC). Results: Our review highlights critical role genetic testing (GT) identifying high-risk individuals (HRIs), germline pathogenic variants (PVs) found up 20% Since implementation next-generation sequencing (NGS) panels 2014, detection capabilities have been significantly enhanced. HRIs can be included screening programs that facilitate early PDAC. Early strategies, including use microribonucleic acid (miRNAs) signatures novel imaging techniques like hyperpolarized 13C-magnetic resonance spectroscopy (MRS) shown promising results. The identification or mutations homologous recombination (HR) genes plays predictive response various treatments, prolonging patient survival. Discussion: Universal PDAC, as recommended by National Comprehensive Cancer Network (NCCN), now standard practice, facilitating at-risk enabling targeted surveillance intervention. Multidisciplinary management, integrating counseling, imaging, gastrointestinal services, essential optimizing outcomes. Conclusions: Advances biomarker research transforming landscape PC management. personalized treatment strategies pivotal improving rates. Ongoing multi-institutional efforts crucial validating biomarkers developing preventive measures, ultimately aiming reduce burden this aggressive cancer.

Language: Английский

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BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

International Journal of Cancer, Journal Year: 2019, Volume and Issue: 145(11), P. 2974 - 2985

Published: April 10, 2019

Prostate cancer (PCa) is the second most common malignancy and sixth leading cause of cancer‐related death among men worldwide. carcinogenesis driven by accumulation genetic epigenetic aberrations, which regulate cell transition between a stem‐ nonstem‐cell state accelerate tumor evolution. Elevated expression enhancer zeste homolog 2 (EZH2) histone methyltransferase, core member polycomb repressive complex (PRC2), results in progression through methylation‐driven cells dedifferentiation. Previous studies demonstrated that suppressor breast 1 (BRCA1) negative regulator PRC2‐dependent H3K27 methylation. Our recent revealed inhibition EZH2‐mediated methylation radiosensitizes prostate stem (CSCs) population. However, link BRCA1 EZH2 regulation CSCs remains elusive. Present study are coregulated patients’ tumors PCa lines, cooperate CSC phenotype properties. Knockdown significantly increases number size spheres. Inhibition leads to an increase aldehyde dehydrogenase (ALDH)‐positive population is, at least partially, attributed upregulation ALDH1A3 protein. Treatment with global inhibitor 3‐Deazaneplanocin A abrogates this regulation, downregulates has inhibitory effect on tumorigenic properties radioresistant vivo . We found EZH2/BRCA1 signaling mechanisms play important role maintenance may be promising target for treatment.

Language: Английский

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