scholarly journals Wee1 Kinase: A Potential Target to Overcome Tumor Resistance to Therapy

2021 ◽  
Vol 22 (19) ◽  
pp. 10689
Author(s):  
Francesca Esposito ◽  
Raffaella Giuffrida ◽  
Gabriele Raciti ◽  
Caterina Puglisi ◽  
Stefano Forte
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Tumor Cells ◽  
Mitotic Catastrophe ◽  
Small Subset ◽  
Tumor Resistance ◽  
Tumor Initiating Cells ◽  
Damage Repair ◽  
Cycle Regulation ◽  
Enzymatic Machinery

During the cell cycle, DNA suffers several lesions that need to be repaired prior to entry into mitosis to preserve genome integrity in daughter cells. Toward this aim, cells have developed complex enzymatic machinery, the so-called DNA damage response (DDR), which is able to repair DNA, temporarily stopping the cell cycle to provide more time to repair, or if the damage is too severe, inducing apoptosis. This DDR mechanism is considered the main source of resistance to DNA-damaging therapeutic treatments in oncology. Recently, cancer stem cells (CSCs), which are a small subset of tumor cells, were identified as tumor-initiating cells. CSCs possess self-renewal potential and persistent tumorigenic capacity, allowing for tumor re-growth and relapse. Compared with cancer cells, CSCs are more resistant to therapeutic treatments. Wee1 is the principal gatekeeper for both G2/M and S-phase checkpoints, where it plays a key role in cell cycle regulation and DNA damage repair. From this perspective, Wee1 inhibition might increase the effectiveness of DNA-damaging treatments, such as radiotherapy, forcing tumor cells and CSCs to enter into mitosis, even with damaged DNA, leading to mitotic catastrophe and subsequent cell death.

scholarly journals Pyrrolizidine alkaloids cause cell cycle and DNA damage repair defects as analyzed by transcriptomics in cytochrome P450 3A4-overexpressing HepG2 clone 9 cells

2021 ◽  
Author(s):  
Sara Abdelfatah ◽  
Janine Naß ◽  
Caroline Knorz ◽  
Sabine M. Klauck ◽  
Jan-Heiner Küpper ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Regulation ◽  
Pyrrolizidine Alkaloids ◽  
Dna Damage Repair ◽  
Cytochrome P450 3A4 ◽  
Limit Values ◽  
Damage Repair ◽  
Chromosome Congression ◽  
Cycle Regulation

AbstractPyrrolizidine alkaloids (PAs) are a large group of highly toxic chemical compounds, which are found as cross-contaminants in numerous food products (e.g., honey), dietary supplements, herbal teas, and pharmaceutical herbal medicines. PA contaminations are responsible for serious hepatotoxicity and hepatocarcinogenesis. Health authorities have to set legal limit values to guarantee the safe consumption of plant-based nutritional and medical products without harmful health. Toxicological and chemical analytical methods are conventionally applied to determine legally permitted limit values for PAs. In the present investigation, we applied a highly sensitive transcriptomic approach to investigate the effect of low concentrations of five PAs (lasiocarpine, riddelliine, lycopsamine, echimidine, and monocrotaline) on human cytochrome P450 3A4-overexpressing HepG2 clone 9 hepatocytes. The transcriptomic profiling of deregulated gene expression indicated that the PAs disrupted important signaling pathways related to cell cycle regulation and DNA damage repair in the transfected hepatocytes, which may explain the carcinogenic PA effects. As PAs affected the expression of genes that involved in cell cycle regulation, we applied flow cytometric cell cycle analyses to verify the transcriptomic data. Interestingly, PA treatment led to an arrest in the S phase of the cell cycle, and this effect was more pronounced with more toxic PAs (i.e., lasiocarpine and riddelliine) than with the less toxic monocrotaline. Using immunofluorescence, high fractions of cells were detected with chromosome congression defects upon PA treatment, indicating mitotic failure. In conclusion, the tested PAs revealed threshold concentrations, above which crucial signaling pathways were deregulated resulting in cell damage and carcinogenesis. Cell cycle arrest and DNA damage repair point to the mutagenicity of PAs. The disturbance of chromosome congression is a novel mechanism of Pas, which may also contribute to PA-mediated carcinogenesis. Transcriptomic, cell cycle, and immunofluorescence analyses should supplement the standard techniques in toxicology to unravel the biological effects of PA exposure in liver cells as the primary target during metabolization of PAs. Graphical abstract

scholarly journals A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Andrea Ghelli Luserna di Rorà ◽  
Claudio Cerchione ◽  
Giovanni Martinelli ◽  
Giorgia Simonetti
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Damage Identification ◽  
Cell Cycle Checkpoints ◽  
Business Regulation ◽  
Damage Repair ◽  
Damage Response ◽  
Cycle Regulation

Abstract The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed. Among them, the most promising ones target the WEE1 kinase family, which has a crucial role in cell cycle regulation and DNA damage identification and repair in both nonmalignant and cancer cells. This review recapitulates and discusses the most recent findings on the biological function of WEE1/PKMYT1 during the cell cycle and in the DNA damage repair, with a focus on their dual role as tumor suppressors in nonmalignant cells and pseudo-oncogenes in cancer cells. We here report the available data on the molecular and functional alterations of WEE1/PKMYT1 kinases in both hematological and solid tumors. Moreover, we summarize the preclinical information on 36 chemo/radiotherapy agents, and in particular their effect on cell cycle checkpoints and on the cellular WEE1/PKMYT1-dependent response. Finally, this review outlines the most important pre-clinical and clinical data available on the efficacy of WEE1/PKMYT1 inhibitors in monotherapy and in combination with chemo/radiotherapy agents or with other selective inhibitors currently used or under evaluation for the treatment of cancer patients.

scholarly journals Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 750
Author(s):  
Kiyohiro Ando ◽  
Akira Nakagawara
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Mitotic Catastrophe ◽  
Malignant Neoplasms ◽  
Checkpoint Kinases ◽  
Molecular Features ◽  
Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

scholarly journals Human POLD1 modulates cell cycle progression and DNA damage repair

2015 ◽  
Vol 16 (1) ◽  
Author(s):  
Jing Song ◽  
Ping Hong ◽  
Chengeng Liu ◽  
Yueqi Zhang ◽  
Jinling Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Dna Damage Repair ◽  
Cycle Progression ◽  
Damage Repair

scholarly journals Genomic hallmarks of cellular dormancy in cancer and therapeutic implications

2021 ◽  
Author(s):  
Maria Secrier ◽  
Anna Wiecek ◽  
Stephen Cutty ◽  
Daniel Kornai ◽  
Mario Parreno-Centeno ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Therapy Resistance ◽  
Therapeutic Resistance ◽  
Epigenetic Mechanisms ◽  
Therapeutic Implications ◽  
Damage Repair ◽  
Repair Deficiency ◽  
Cell Data ◽  
Cell Cycle Kinase

Abstract Therapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative, quiescent or ‘dormant’ state, which is difficult to capture and whose mutational drivers remain largely unknown. We developed methodology to uniquely identify this state from transcriptomic signals and characterised its prevalence and genomic constraints in solid primary tumours. We show dormancy preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We uncover novel genomic dependencies of this process, including the amplification of the centrosomal gene CEP89 as a driver of dormancy impairment. Lastly, we demonstrate that dormancy underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single cell data, and propose a signature of dormancy-linked therapeutic resistance to further study and clinically track this state.

Sign in / Sign up

Export Citation Format

Share Document