scholarly journals Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Satoshi Tanida ◽  
Tsutomu Mizoshita ◽  
Keiji Ozeki ◽  
Hironobu Tsukamoto ◽  
Takeshi Kamiya ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Damage ◽  
Molecular Mechanisms ◽  
Cisplatin Resistance ◽  
Drug Uptake ◽  
Apoptotic Pathway ◽  
Damage Recognition ◽  
Cisplatin Sensitivity ◽  
Induced Apoptosis ◽  
Dna Damage Recognition

Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. Cisplatin forms inter- and intrastrand crosslinked DNA adducts and its cytotoxicity is mediated by propagation of DNA damage recognition signals to downstream pathways involving ATR, p53, p73, and mitogen-activated protein kinases, ultimately resulting in apoptosis. Cisplatin resistance arises through a multifactorial mechanism involving reduced drug uptake, increased drug inactivation, increased DNA damage repair, and inhibition of transmission of DNA damage recognition signals to the apoptotic pathway. In addition, a new mechanism has recently been revealed, in which the oncoprotein c-Myc suppresses bridging integrator 1 (BIN1), thereby releasing poly(ADP-ribose)polymerase 1, which results in increased DNA repair activity and allows cancer cells to acquire cisplatin resistance. The present paper focuses on the molecular mechanisms of cisplatin-induced apoptosis and of cisplatin resistance, in particular on the involvement of BIN1 in the maintenance of cisplatin sensitivity.

scholarly journals Cationic Channel TRPV2 Overexpression Promotes Resistance to Cisplatin-Induced Apoptosis in Gastric Cancer Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Simona Laurino ◽  
Pellegrino Mazzone ◽  
Vitalba Ruggieri ◽  
Pietro Zoppoli ◽  
Giovanni Calice ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Flow Cytometry ◽  
Cell Lines ◽  
Cisplatin Resistance ◽  
Inverse Correlation ◽  
Gastric Cancer Cells ◽  
Aberrant Expression ◽  
Cisplatin Sensitivity ◽  
Induced Apoptosis

Gastric cancer (GC) is characterized by poor efficacy and modest clinical impact of current therapies, in which apoptosis evasion is relevant. Intracellular calcium homeostasis dysregulation is associated with apoptosis escaping, and aberrant expression of calcium regulator genes could promote GC drug resistance. Since we previously found a prognostic value for TRPV2 calcium channel expression in GC, we aimed to characterize the role of TRPV2 in cisplatin resistance. Using the TCGA-STAD dataset, we performed a differential gene expression analysis between GC samples in upper and lower tertiles of TRPV2 expression, and then through a gene set analysis, we highlighted the enriched ontology and canonical pathways. We used qRT-PCR to assess TRPV2 expression in three GC cell lines and flow cytometry to evaluate cisplatin-induced cell death rates. Calcium green-1-AM assay was used to estimate differences in intracellular Ca2+ concentrations after inhibition of TRPV2. We engineered AGS cell line to overexpress TRPV2 and used confocal microscopy to quantify its overexpression and localization and flow cytometry to evaluate their sensitivity to cisplatin. Consistent with our hypothesis, among enriched gene sets, we found a significant number of those involved in the regulation of apoptosis. Subsequently, we found an inverse correlation between TRPV2 expression and sensitivity to cisplatin in GC cell lines. Moreover, we demonstrated that inhibition of TRPV2 activity by tranilast blocks the efflux of Ca2+ ions and, in combination with cisplatin, induced a significant increase of apoptotic cells (p = 0.004). We also demonstrated that TRPV2 exogenous expression confers a drug-resistant phenotype, and that tranilast is able to revert this phenotype, restoring cisplatin sensitivity. Our findings consistently suggested that TRPV2 could be a potential target for overcoming cisplatin resistance by promoting apoptosis. Notably, our data are a prerequisite for the potential reposition of tranilast to the treatment of GC patients and anticipate the in vivo evaluation.

scholarly journals Targeting Protein-Protein Interactions in the DNA Damage Response Pathways for Cancer Chemotherapy

2021 ◽  
Author(s):  
Kerry Silva McPherson ◽  
Dmitry Korzhnev
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Interactions ◽  
Cell Cycle Progression ◽  
Protein Protein Interactions ◽  
Cycle Progression ◽  
Damage Recognition ◽  
Damage Response ◽  
Cellular Dna ◽  
Dna Damage Recognition

Cellular DNA damage response (DDR) is an extensive signaling network that orchestrates DNA damage recognition, repair and avoidance, cell cycle progression and cell death. DDR alternation is a hallmark of...

scholarly journals SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia

Blood ◽  
2017 ◽  
Vol 130 (24) ◽  
pp. 2631-2641 ◽  
Author(s):  
Brenton G. Mar ◽  
S. Haihua Chu ◽  
Josephine D. Kahn ◽  
Andrei V. Krivtsov ◽  
Richard Koche ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mutation Rate ◽  
Histone 3 ◽  
Damage Recognition ◽  
Key Points ◽  
Damage Response ◽  
Dna Damage Recognition ◽  
Resistance To Chemotherapy

Key Points Alterations of SETD2, a histone 3 lysine 36 trimethyl (H3K36me3) transferase leads to resistance to DNA damaging-chemotherapy in leukemia. Low H3K36me3 levels impair DNA damage response and increase mutation rate, which may be targeted by H3K36me3 demethylase inhibition.

The role of chromatin proteins in DNA damage recognition and repair Mini-review

2005 ◽  
Vol 125 (1-2) ◽  
pp. 119-126 ◽  
Author(s):  
Piotr Widlak ◽  
Monika Pietrowska ◽  
Joanna Lanuszewska
Keyword(s):  
Dna Damage ◽  
Damage Recognition ◽  
Chromatin Proteins ◽  
Dna Damage Recognition

HUMAN CELLULAR DNA DAMAGE RECOGNITION PROTEINS

1991 ◽  
pp. 219
Author(s):  
E.N. HUGHES ◽  
B.N. ENGELSBERG
Keyword(s):  
Dna Damage ◽  
Damage Recognition ◽  
Cellular Dna ◽  
Dna Damage Recognition
Sign in / Sign up

Export Citation Format

Share Document