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Rapid development of resistance to tumor necrosis factor alpha on Ishikawa human endometrial carcinoma cells
C Marth1, L C Fuith, E Müller-Holzner
1Department of Obstetrics and Gynecology, Innsbruck University Clinic, Austria.
Abstract:
The human endometrial adenocarcinoma cells IK were found to be highly susceptible for TNF but rapidly developed a resistance to this cytokine. Inhibitors of RNA transcription or protein biosynthesis could not overcome this resistance. Moreover TNF resistance was not associated with increased resistance to hydrogen peroxide. The resistant phenotype remained stable and was not communicated to neighbouring cells in a paracrine manner. The TNF treatment did not induce a multidrug resistance on IK cells. Nude mice bearing xenotransplanted endometrial carcinoma cells did not benefit from TNF treatment.
Insights
Human endometrial cancer cells initially responded to tumor necrosis factor (TNF) but quickly became resistant. This resistance was stable, not transferable, and unaffected by standard inhibitors, limiting TNF
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Human endometrial adenocarcinoma IK cells exhibit initial susceptibility to tumor necrosis factor (TNF).
- Rapid development of resistance to TNF in these cancer cells poses a therapeutic challenge.
Purpose of the Study:
- To investigate the mechanisms and characteristics of TNF resistance in human endometrial adenocarcinoma IK cells.
- To determine the therapeutic efficacy of TNF in a xenograft model of endometrial carcinoma.
Main Methods:
- Exposure of IK cells to TNF to induce resistance.
- Assessment of resistance using RNA transcription and protein biosynthesis inhibitors.
- Evaluation of cross-resistance to hydrogen peroxide.
- Analysis of resistance stability and intercellular communication.
- Testing TNF efficacy in nude mice bearing xenotransplanted endometrial carcinoma cells.
Main Results:
- IK cells rapidly developed stable resistance to TNF.
- Resistance was not overcome by inhibitors of RNA transcription or protein biosynthesis.
- TNF resistance did not confer cross-resistance to hydrogen peroxide.
- The resistant phenotype was stable and not communicated to neighboring cells.
- TNF treatment showed no therapeutic benefit in a preclinical xenograft model.
Conclusions:
- TNF resistance in endometrial adenocarcinoma cells is a stable, intrinsic property.
- Standard molecular inhibitors do not reverse TNF resistance.
- TNF is ineffective for treating endometrial carcinoma in vivo.
