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[14-3-3ζ protein mediates gemcitabine resistance in NK/T-cell lymphoma]
1Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Abstract:
Objective: To explore the molecular mechanisms of 14-3-3ζ in gemcitabine resistance in extranodal NK/T-cell lymphoma, nasal type (ENKTL) . Methods: The effects of cell proliferation and invasion were detected by cell counting kit-8 (CCK-8) assay and transwell assay. YTS cells were exposed to gradually increased concentrations of gemcitabine to establish gemcitabine-resistant YTS cells (YTS-gem) in vitro. 14-3-3ζ specific siRNA lentiviral vector was transfected into YTS and YTS-gem cells to downregulate 14-3-3ζ expression, and stable transfected cell clones were screened. The protein expression was determined by Western blot. Results: ①14-3-3ζ expression was significantly up-regulated in gemcitabine resistant YTS-gem cells, comparing with that of YTS cells (P<0.05) . ②The results of CCK-8 and transwell assay showed that downregulation of 14-3-3ζ significantly reduced the cell proliferation and invasion abilities (P<0.05) . ③Downregulation of 14-3-3ζ could restore gemcitabine sensitivity in gemcitabine resistant YTS-gem cells (P<0.05) . ④Western blotting results showed that knockdown of 14-3-3ζ significantly upregulated pro-apoptotic Bax, and downregulated anti-apoptotic Bcl-2, Caspase-3, cleaved caspase-3, Cyclin D1 in gemcitabine-resistant YTS-gem cells (P<0.05) . There was no significant difference in p53 ang P-gp expression levels. Conclusions: 14-3-3ζ was upregulated in gemcitabine resistant YTS cells. Overexpression of 14-3-3ζ promoted cell proliferation and enhanced cell migration. 14-3-3ζ contributed to gemcitabine resistance to ENKTL through anti-apoptosis.
Insights
14-3-3ζ protein is upregulated in gemcitabine-resistant extranodal NK/T-cell lymphoma (ENKTL) cells. Downregulating 14-3-3ζ restores sensitivity to gemcitabine by reducing proliferation and promoting apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is an aggressive non-Hodgkin lymphoma.
- Gemcitabine is a key chemotherapeutic agent, but resistance remains a significant clinical challenge.
- The molecular mechanisms underlying gemcitabine resistance in ENKTL require further elucidation.
Purpose of the Study:
- To investigate the role of 14-3-3ζ in the development of gemcitabine resistance in ENKTL.
- To explore the molecular pathways through which 14-3-3ζ influences cell proliferation, invasion, and apoptosis in gemcitabine-resistant ENKTL cells.
Main Methods:
- Establishment of gemcitabine-resistant YTS cells (YTS-gem) in vitro.
- Downregulation of 14-3-3ζ expression using siRNA lentiviral vectors.
- Assessment of cell proliferation and invasion via CCK-8 and Transwell assays.
- Western blot analysis to determine protein expression levels.
Main Results:
- 14-3-3ζ expression was significantly upregulated in gemcitabine-resistant YTS-gem cells compared to sensitive YTS cells.
- Downregulation of 14-3-3ζ reduced cell proliferation and invasion, and restored sensitivity to gemcitabine.
- Knockdown of 14-3-3ζ increased pro-apoptotic Bax and decreased anti-apoptotic Bcl-2, Caspase-3, cleaved caspase-3, and Cyclin D1.
Conclusions:
- 14-3-3ζ is upregulated in gemcitabine-resistant ENKTL and promotes cell proliferation and migration.
- 14-3-3ζ contributes to gemcitabine resistance in ENKTL by inhibiting apoptosis.
- Targeting 14-3-3ζ may represent a therapeutic strategy to overcome gemcitabine resistance in ENKTL.
