Low expression of PRKCDBP promoted cisplatin resistance in lung adenocarcinoma by DNMT1 and TNF‑α
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Updated: Oct 8, 2026
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Jiali Fu1, Huixin Zhou1, Jie Chen2
1Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China.
Abstract:
The aim of the present study was to explore the mechanism of protein kinase C delta binding protein (PRKCDBP) promoting cisplatin resistance in lung adenocarcinoma (LAD). The PRKCDBP expression level was herein detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). We overexpressed PRKCDBP and tumor necrosis factor‑α (TNF‑α) in A549/DDP cell line, DNMT1 in A549 cells and siRNA TNF‑α in A549 cells with lentivirus‑mediated technique, and then, analyzed their biological diversification. The results showed a significantly lower expression level of PRKCDBP was lowly expressed in the A549/DDP cell line and LAD tissues than that in A549 cells and adjacent cancer tissues (P<0.05 and P<0.01), while the DNMT1 mRNA level was remarkably increased (P=0.000) and the promoter of PRKCDBP was hypermethylated in the A549/DDP cell line. Additionally, DNMT1 mRNA level in cisplatin‑insensitive group was markedly higher than that in cisplatin‑sensitive group (t=7.233, P<0.0001), while PRKCDBP mRNA level in cisplatin insensitive group was notably lower than that in cisplatin‑sensitive group (t=8.784, P<0.0001). The results showed that PRKCDBP mRNA level was significantly elevated following treatment with 5 µM decitabine for 24 h (P<0.0001), while the DNMT1 mRNA level was notably reduced (P=0.000). When PRKCDBP was overexpressed, the DNMT1 mRNA level was markedly decreased (P=0.007), the rate of proliferation (P<0.05 or P<0.01), IC50 of cisplatin (P<0.001), G2/M phase and S phase cells were obviously reduced (P<0.001), while G0/G1 phase cells, apoptosis (P<0.001) distinctly increased, but migration ability did not significantly change. TNF‑α overexpression resulted in an increase of PRKCDBP mRNA level (P<0.001), while TNF‑α siRNA led to PRKCDBP mRNA level distinctly reduced (P<0.001). Overexpression of DNMT1 improved IC50 in A549 cells. Thus, findings of the present study ascertained the promoter of PRKCDBP was hypermethylated in A549/DDP cells. In conclusion, low expression of PRKCDBP promoted cisplatin resistance in LAD by DNMT1 and TNF‑α.
Insights
Low expression of protein kinase C delta binding protein (PRKCDBP) promotes cisplatin resistance in lung adenocarcinoma (LAD) by increasing DNMT1 and TNF-α. Restoring PRKCDBP levels can overcome this resistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Lung adenocarcinoma (LAD) exhibits resistance to cisplatin chemotherapy.
- The precise mechanisms underlying this chemoresistance require further elucidation.
Purpose of the Study:
- To investigate the role of protein kinase C delta binding protein (PRKCDBP) in promoting cisplatin resistance in LAD.
- To explore the underlying molecular mechanisms involving DNMT1 and TNF-α.
Main Methods:
- Quantitative reverse transcription PCR (RT-qPCR) to measure PRKCDBP and DNMT1 mRNA levels.
- Lentivirus-mediated overexpression of PRKCDBP and tumor necrosis factor-α (TNF-α), and siRNA-mediated knockdown of TNF-α in A549/DDP and A549 cell lines.
- Analysis of cell proliferation, IC50 of cisplatin, cell cycle distribution, apoptosis, and migration.
- Assessment of PRKCDBP promoter methylation status.
Main Results:
- PRKCDBP expression was significantly lower in cisplatin-resistant LAD cells (A549/DDP) and tissues compared to sensitive cells and adjacent tissues.
- DNMT1 mRNA levels were elevated, and the PRKCDBP promoter was hypermethylated in resistant cells.
- Overexpression of PRKCDBP decreased DNMT1 levels, reduced proliferation and cisplatin IC50, and increased apoptosis.
- TNF-α influenced PRKCDBP expression, suggesting its involvement in the resistance mechanism.
Conclusions:
- Hypermethylation of the PRKCDBP promoter and increased DNMT1 contribute to low PRKCDBP expression in cisplatin-resistant LAD.
- Low PRKCDBP expression promotes cisplatin resistance in LAD, mediated by DNMT1 and TNF-α.
- Targeting PRKCDBP or related pathways may offer therapeutic strategies for overcoming cisplatin resistance in LAD.
