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Published on: January 4, 2012
Petite Integration Factor 1 knockdown enhances gemcitabine sensitivity in pancreatic cancer cells via increasing DNA
Kun Wang1, Xiangdong Hua1, Xibo Fu1
1Department of Hepatobiliary and Pancreatic Surgery, Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China.
Abstract:
Chemoresistance is still a vital obstacle in various tumors chemotherapy. This study aimed to explore the role of Petite Integration Factor 1 (PIF1) in the sensitivity of gemcitabine response to pancreatic cancer cells. Gene Expression Profiling Interactive Analysis (GEPIA) database was employed for evaluating the level of PIF1 in pancreatic cancer tissues and normal tissues. The mRNA level of PIF1 was detected via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. The relative protein expression of PIF1, cleaved caspase-3, and phosphorylated histone H2Ax (γH2Ax) was assessed through western blot. Cell viability and apoptosis were assessed via Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. Moreover, lactate dehydrogenase (LDH) release and caspase-3 activity were determined via the corresponding LDH Cytotoxicity Assay Kit and caspase-3 colorimetric assay kit. PIF1 expression was upregulated in pancreatic cancer tissues and cells. Knockdown of PIF1 exhibited the repressive impact on the viability of AsPC-1 and PANC-1 cells. PIF1 knockdown enhanced LDH release and apoptosis in both AsPC-1 and PANC-1 cells. PIF1 downregulation could augment the sensitivity of gemcitabine in pancreatic cancer cells, as evidenced by lower cell viability and higher LDH release and apoptosis rate after knocking down PIF1 in gemcitabine-treated pancreatic cancer cells relative to pancreatic cancer cells treated with gemcitabine alone. Moreover, PIF1 knockdown increased γH2Ax protein expression and DNA damage, and gemcitabine treatment-induced DNA damage in AsPC-1 and PANC-1 cells was exacerbated by PIF1 silencing. Furthermore, gemcitabine treatment-caused increase of DNA damage was alleviated by PIF1 overexpression; whereas, this effect of PIF1 upregulation was reversed by thymidine, a DNA synthesis inhibitor. In addition, the decreased gemcitabine sensitivity response to pancreatic cancer cells caused by PIF1 upregulation was also hindered by thymidine treatment. In conclusion, PIF1 silencing enhanced gemcitabine sensitivity response to pancreatic cancer cells through aggrandizing DNA damage.
Insights
Silencing Petite Integration Factor 1 (PIF1) enhances gemcitabine sensitivity in pancreatic cancer cells by increasing DNA damage. PIF1 upregulation reduces gemcitabine effectiveness, while its knockdown improves treatment response.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chemoresistance remains a significant challenge in pancreatic cancer chemotherapy.
- Petite Integration Factor 1 (PIF1) has emerged as a potential factor influencing treatment response.
Purpose of the Study:
- To investigate the role of PIF1 in gemcitabine sensitivity in pancreatic cancer cells.
- To determine how PIF1 expression affects chemotherapy response and DNA damage.
Main Methods:
- Utilized Gene Expression Profiling Interactive Analysis (GEPIA) for PIF1 expression analysis.
- Employed RT-qPCR, western blot, CCK-8 assay, flow cytometry, LDH assay, and caspase-3 activity assays.
- Assessed PIF1 knockdown and overexpression effects on cell viability, apoptosis, and DNA damage.
Main Results:
- PIF1 expression was significantly upregulated in pancreatic cancer tissues and cells.
- PIF1 knockdown reduced cell viability and increased apoptosis and LDH release.
- PIF1 silencing enhanced gemcitabine sensitivity by increasing DNA damage (γH2Ax expression).
- PIF1 overexpression decreased gemcitabine sensitivity, an effect reversed by thymidine.
Conclusions:
- PIF1 acts as a negative regulator of gemcitabine sensitivity in pancreatic cancer.
- PIF1 silencing represents a potential strategy to overcome chemoresistance and improve gemcitabine efficacy.
- Targeting PIF1 may enhance DNA damage and therapeutic outcomes in pancreatic cancer treatment.
