Yalçın ERZURUMLU, Hatice Kübra DOĞAN, Deniz ÇATAKLI

UPR'NİN IRE1α/XBP-1 DALININ GSK2850163 ARACILI İNHİBİSYONU MEME KANSERİ HÜCRELERİNDE TAMOKSİFENE DUYARLILIĞI ARTIRIR

Amaç: Tamoksifen meme kanserine karşı önde gelen tedavi olarak kullanılmaktadır ve son 40 yıldır yaygın olarak uygulanmaktadır. Ancak tamoksifene karşı direnç gelişimi meme kanserinin etkin tedavisindeki en büyük sınırlamalardan birisidir. Çalışmamızın amacı, UPR'nin IRE1α/XBP-1 dalının GSK2850163 tarafından bloke edilmesinin, tamoksifene dirençli MCF-7 hücrelerinin kanserojen yeteneğini verimli bir şekilde sınırlayıp sınırlamadığını araştırmaktır. Gereç ve Yöntem: İlk olarak, MCF-7 hücrelerinin düzenli olarak tamoksifene maruz bırakılmasıyla tamoksifene dirençli meme kanseri hücreleri elde edildi. GSK2850163'ün biyokimyasal aktivitesi, immünoblotlama ve qRT-PCR ile doğrulandı. GSK2850163 ve tamoksifenin kombine tedavisinin tamoksifene dirençli meme kanseri hücrelerinin proliferasyon, invazyon, migrasyon ve koloni oluşturma yetenekleri üzerindeki olası etkileri sırasıyla WST-1 tabanlı proliferasyon testi, Boyden-chamber invazyon testi, yara iyileştirme testi ve plaka koloni oluşturma yöntemleri ile değerlendirildi. Sonuç ve Tartışma: Çalışmamızda IRE1α/XBP-1’in GSK2850163 tarafından spesifik blokajının, tamoksifene dirençli MCF-7 hücrelerinin kanserojen yeteneğini verimli bir şekilde sınırladığını gösterdik. Ayrıca, tamoksifen ve GSK2850163 ile birlikte tedavi, tamoksifenin anti-kanserojen özelliğini geliştirerek meme kanseri hücrelerinin istila, göç ve koloni oluşturma yeteneklerini önemli ölçüde azalttı. Sonuçlarımız, IRE1α/XBP-1 inhibitörlerinin meme kanseri tedavisinde güçlü terapötikler olabileceğini önermektedir.

Anahtar Kelimeler:

: Meme Kanseri, GSK2850163, IRE1α/XBP-1, Tamoksifen, UPR

INHIBITION OF IRE1α/XBP-1 BRANCH OF UPR BY GSK2850163 DRIVES THE SENSITIVITY TO TAMOXIFEN IN BREAST CANCER CELLS

Objective: Tamoxifen is used as the leading treatment against breast cancer and has been broadly applied for the last 40 years. However, resistance development against tamoxifen is one of the major limitations in the effective treatment of breast cancer. The aim of our study was to investigate whether blockage of the IRE1α/XBP-1 branch of UPR by GSK2850163 efficiently limited the carcinogenic ability of tamoxifen-resistant MCF-7 cells. Material and Method: Firstly, tamoxifen-resistant breast cancer cells were obtained by regularly exposing MCF-7 cells to tamoxifen. The biochemical activity of GSK2850163 was confirmed by immunoblotting and qRT-PCR. The possible effect of combined treatment of GSK2850163 and tamoxifen on proliferation, invasion, migration, and colony formation abilities of tamoxifen-resistant breast cancer cells were evaluated by using WST-1 based proliferation assay, Boyden-chamber invasion test, wound-healing assay, and plate colony formation methods, respectively. Result and Discussion: Here, we showed that specific blockage of the IRE1α/XBP-1 by GSK2850163 efficiently limited the carcinogenic ability of tamoxifen-resistant MCF-7 cells. Moreover, co-treatment with tamoxifen and GSK2850163 significantly reduced the invasion, migration, and colony formation abilities of breast cancer cells through improved the anti-carcinogenic property of tamoxifen. Our results strongly suggested that IRE1α/XBP-1 inhibitors may be potent therapeutics in breast cancer treatment.

Keywords:

Breast Cancer, GSK2850163, IRE1α/XBP-1, Tamoxifen, UPR,

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