Chemoresistance of PRAME-expressing melanoma cell can be resolved with help of bortezomib

• Published in: Uspehi molekulârnoj onkologii Vol. 5; no. 4; pp. 131 - 134
• Main Authors: Misyurin, V. A., Kalenichenko, D. V., Rudakova, A. A., Finashutina, Yu. P., Lyzhko, N. A., Tikhonova, V. V., Kesaeva, L. A., Solopova, O. N., Misyurina, A. Е., Velikanov, A. N., Baryshnikovа, M. А., Misyurin, A. V.
• Format: Journal Article
• Language: English; Russian
• Published: ABV-press 04-01-2019
• Subjects: bortezomib; cisplatin; dexamethasone; drug resistance; melanoma; prame
• ISSN: 2313-805X; 2413-3787
• DOI: 10.17650/2313-805X-2018-5-4-131-134

Background. PRAME gene spontaneous expression is frequently observed in a cancer cell. The protein encoded by this gene increases  the viability of tumour cell. NF-κB signalling pathway takes part in PRAME upregulation. It proposes, that stress conditions may increase the expression level of PRAME in the tumour cell and increase cell’s viability after it. We hypothesized that this phenomenon determines chemoresistance of PRAME-expressing cell, which can be overcome by NF-κB inhibitors, such as bortezomib.
Materials and methods. We incubated A875 melanoma cells with cisplatin, bortezomib and dexamethasone, as well as with a mixture  of cisplatin with bortezomib and cisplatin with dexamethasone within 24 hours. To assess the cytotoxicity of these combinations MTT-test was used. For evaluation of PRAME expression level, real-time polymerase chain reaction was used. All data were analyzed with Wilcoxon test for coupled samples.
Results. It was found that cisplatin and dexamethasone increased an expression level of PRAME compared to control (p <0.03). The addition of dexamethasone to cisplatin reduced cytotoxic effect of cisplatin. Bortezomib has a cytotoxic effect, but it did not increase the activity  of PRAME gene (p = 0.12). PRAME gene activity in cells incubated with a mixture of cisplatin and bortezomib was observed at a lower level in comparison with cells incubated with cisplatin (p = 0.0277).
Conclusion. The results of experiments show that an increase of PRAME expression level reduces the sensitivity of melanoma cells to the cytotoxic effect of cisplatin. PRAME activity increases under stress conditions. Using of bortezomib can inhibit the growth of PRAME expression and makes the tumour cell more vulnerable to cytotoxic agents. On the other hand, dexamethasone may increase a resistance  of PRAME-expressing cell to cytotoxic effects.