scholarly journals Human ALKBH6 Is Required for Maintenance of Genomic Stability and Promoting Cell Survival During Exposure of Alkylating Agents in Pancreatic Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Shengyuan Zhao ◽  
Rodan Devega ◽  
Aaliyah Francois ◽  
Dawit Kidane
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cell Survival ◽  
Cancer Cells ◽  
Alkylating Agent ◽  
Alkylating Agents ◽  
The Cancer Genome Atlas ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Dna Repair Gene

Alpha-ketoglutarate-dependent dioxygenase (ALKBH) is a DNA repair gene involved in the repair of alkylating DNA damage. There are nine types of ALKBH (ALKBH1-8 and FTO) identified in humans. In particular, certain types of ALKBH enzymes are dioxygenases that directly reverse DNA methylation damage via transfer of a methyl group from the DNA adduct onto α-ketoglutarate and release of metabolic products including succinate and formaldehyde. Here, we tested whether ALKBH6 plays a significant role in preventing alkylating DNA damage and decreasing genomic instability in pancreatic cancer cells. Using an E. coli strain deficient with ALKB, we found that ALKBH6 complements ALKB deficiency and increases resistance after alkylating agent treatment. In particular, the loss of ALKBH6 in human pancreatic cancer cells increases alkylating agent-induced DNA damage and significantly decreases cell survival. Furthermore, in silico analysis from The Cancer Genome Atlas (TCGA) database suggests that overexpression of ALKBH6 provides better survival outcomes in patients with pancreatic cancer. Overall, our data suggest that ALKBH6 is required to maintain the integrity of the genome and promote cell survival of pancreatic cancer cells.

scholarly journals APE2 Is a General Regulator of the ATR-Chk1 DNA Damage Response Pathway to Maintain Genome Integrity in Pancreatic Cancer Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Md Akram Hossain ◽  
Yunfeng Lin ◽  
Garrett Driscoll ◽  
Jia Li ◽  
Anne McMahon ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Human Pancreatic Cancer ◽  
Genome Integrity ◽  
Pancreatic Cancer Cells ◽  
Damage Response ◽  
Egg Extracts

The maintenance of genome integrity and fidelity is vital for the proper function and survival of all organisms. Recent studies have revealed that APE2 is required to activate an ATR-Chk1 DNA damage response (DDR) pathway in response to oxidative stress and a defined DNA single-strand break (SSB) in Xenopus laevis egg extracts. However, it remains unclear whether APE2 is a general regulator of the DDR pathway in mammalian cells. Here, we provide evidence using human pancreatic cancer cells that APE2 is essential for ATR DDR pathway activation in response to different stressful conditions including oxidative stress, DNA replication stress, and DNA double-strand breaks. Fluorescence microscopy analysis shows that APE2-knockdown (KD) leads to enhanced γH2AX foci and increased micronuclei formation. In addition, we identified a small molecule compound Celastrol as an APE2 inhibitor that specifically compromises the binding of APE2 but not RPA to ssDNA and 3′-5′ exonuclease activity of APE2 but not APE1. The impairment of ATR-Chk1 DDR pathway by Celastrol in Xenopus egg extracts and human pancreatic cancer cells highlights the physiological significance of Celastrol in the regulation of APE2 functionalities in genome integrity. Notably, cell viability assays demonstrate that APE2-KD or Celastrol sensitizes pancreatic cancer cells to chemotherapy drugs. Overall, we propose APE2 as a general regulator for the DDR pathway in genome integrity maintenance.

scholarly journals Light Stability, Pro-Apoptotic and Genotoxic Properties of Silver (I) Complexes of Metronidazole and 4-Hydroxymethylpyridine against Pancreatic Cancer Cells In Vitro

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3848
Author(s):  
Dominik Żyro ◽  
Agnieszka Śliwińska ◽  
Izabela Szymczak-Pajor ◽  
Małgorzata Stręk ◽  
Justyn Ochocki
Keyword(s):  
Pancreatic Cancer ◽  
Flow Cytometry ◽  
Dna Damage ◽  
Silver Nitrate ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

Antimicrobial properties of silver (I) ion and its complexes are well recognized. However, recent studies suggest that both silver (I) ion and its complexes possess anticancer activity associated with oxidative stress-induced apoptosis of various cancer cells. In this study, we aimed to investigate whether silver nitrate and its complexes with metronidazole and 4-hydroxymethylpyridine exert anticancer action against human pancreatic cancer cell lines (PANC-1 and 1.2B4). In the study, we compared decomposition speed for silver complexes under the influence of daylight and UV-A (ultraviolet-A) rays. We employed the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide) assay to evaluate the cytotoxicity and the alkaline comet assay to determine genotoxicity of silver nitrate and its complexes. Flow cytometry and the Annexin V-FITC/PI apoptosis detection kit were used to detect the apoptosis of human pancreatic cancer cells. We found a dose dependent decrease of both pancreatic cancer cell line viability after exposure to silver nitrate and its complexes. The flow cytometry analysis confirmed that cell death occurred mainly via apoptosis. We also documented that the studied compounds induced DNA damage. Metronidazole and 4-hydroxymethylpyridine alone did not significantly affect viability and level of DNA damage of pancreatic cancer cell lines. Complex compounds showed better stability than AgNO3, which decomposed slower than when exposed to light. UV-A significantly influences the speed of silver salt decomposition reaction. To conclude, obtained data demonstrated that silver nitrate and its complexes exerted anticancer action against human pancreatic cancer cells.

scholarly journals BML-275, an AMPK inhibitor, induces DNA damage, G2/M arrest and apoptosis in human pancreatic cancer cells

2012 ◽  
Vol 41 (6) ◽  
pp. 2227-2236 ◽  
Author(s):  
HONG-QUAN DUONG ◽  
JAE SEOK HWANG ◽  
HEE JEONG KIM ◽  
YEON-SUN SEONG ◽  
INSOO BAE
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

2010 ◽  
Vol 999 (999) ◽  
pp. 1-11
Author(s):  
P. Ulivi ◽  
C. Arienti ◽  
W. Zoli ◽  
M. Scarsella ◽  
S. Carloni ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Antitumor Efficacy ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

scholarly journals Cyathus striatus Extract Induces Apoptosis in Human Pancreatic Cancer Cells and Inhibits Xenograft Tumor Growth In Vivo

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2017
Author(s):  
Lital Sharvit ◽  
Rinat Bar-Shalom ◽  
Naiel Azzam ◽  
Yaniv Yechiel ◽  
Solomon Wasser ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Culture Liquid ◽  
Human Pancreatic Cancer ◽  
P53 Signaling ◽  
Pancreatic Cancer Cells

Pancreatic cancer is a highly lethal disease with limited options for effective therapy and the lowest survival rate of all cancer forms. Therefore, a new, effective strategy for cancer treatment is in need. Previously, we found that a culture liquid extract of Cyathus striatus (CS) has a potent antitumor activity. In the present study, we aimed to investigate the effects of Cyathus striatus extract (CSE) on the growth of pancreatic cancer cells, both in vitro and in vivo. The proliferation assay (XTT), cell cycle analysis, Annexin/PI staining and TUNEL assay confirmed the inhibition of cell growth and induction of apoptosis by CSE. A Western blot analysis demonstrated the involvement of both the extrinsic and intrinsic apoptosis pathways. In addition, a RNAseq analysis revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. The anticancer activity of the CSE was also demonstrated in mice harboring pancreatic cancer cell line-derived tumor xenografts when CSE was given for 5 weeks by weekly IV injections. Our findings suggest that CSE could potentially be useful as a new strategy for treating pancreatic cancer.

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