Investigation of the Effects of Suppression of the IRE1α Arm of the Unfolded Protein Response Signaling Pathway on Tumorigenic Characteristics of PANC-1 Pancreatic Ductal Adenocarcinoma Cells

Öz

Objective: Pancreatic cancer is mean as a group of malignancies originating from cells in the pancreatic tissue. This developing malignancy is named pancreatic ductal adenocarcinoma (PDAC). The survival rate of patients who develop PDAC is very low and is the fourth most common cause of cancer-related death worldwide. Hypoxic and nutrient-deprived conditions of the microenvironment surrounding PDAC tumors have been reported to induce increased basal ER stress in cells. Cells are developed an evolutionarily conserved signal transduction pathway called the Unfolded Protein Response (UPR) that controls ER stress responses in cells, which primary purpose is to restore ER homeostasis. Recent studies have revealed that the UPR signaling pathway contributes to the carcinogenesis process. It has been reported that changes in ER stress and UPR activity are directly related to the development of many types of cancer, including ovarian, prostate, breast, and pancreatic cancer. In our study, the effects of inhibition of IRE1α, one of the three important effector proteins involved in the regulation of the UPR, with a selective inhibitor, MKC-3946, on the tumorigenic properties of PANC-1 cells were investigated.

Material-Method: The biochemical efficiency of MKC-3946 was evaluated by immunoblotting. The effects of MKC-3946 on the tumorigenic ability of PANC-1 cells were investigated by WST-1-based cell proliferation measurement, colony formation assay and wound healing assay.

Results: MKC-3946 treatment significantly suppressed the tumorigenic properties of PANC-1 cells.

Conclusion: Pharmacological targeting of the IRE1α in pancreatic cancer may provide a new therapeutic perspective.

Anahtar Kelimeler

• MKC-3946
• IRE1α
• Pancreas cancer
• UPR

Katlanmamış Protein Yanıtı Sinyal Yolunun IRE1α Kolunun Baskılanmasının PANC-1 Pankreatik Duktal Adenokarsinoma Hücrelerinin Tümörijenik Özellikleri Üzerindeki Etkilerinin İncelenmesi

Öz

Amaç: Pankreas kanseri pankreas dokusundaki hücrelerden orijin alan bir grup malignite olarak ifade edilmektedir. Gelişen bu malignite pankreas duktal adenokarsinomu (PDAC) olarak adlandırılmaktadır. PDAC gelişen hastaların sağ kalım oranları oldukça düşüktür ve dünya genelinde kansere bağlı ölümlerin dördüncü en sık nedenidir. PDAC tümörlerini çevreleyen mikroortamın hipoksik koşulları ve besinden yoksun şartlarının hücrelerde artmış bazal ER stresini uyardığı rapor edilmiştir. Hücrelerde ER stresi yanıtlarını kontrol eden Katlanmamış Protein Yanıtı (UPR) adı verilen ve birincil amacı ER homeostazisini yeniden kurmak olan evrimsel olarak korunmuş bir sinyal iletim yolu geliştirmiştir. Son yıllardaki çalışmalar UPR sinyal yolunun karsinogenez sürecine katkıda bulunduğunu ortaya koymuştur. ER stresi ve UPR aktivitesindeki değişimlerin ovaryum, prostat, meme ve pankreas kanseri de dahil olmak üzere birçok kanser türünün gelişimi ile doğrudan ilişkili olduğu rapor edilmiştir. Çalışmamızda UPR’nin regülasyonunda görev alan üç önemli efektör proteininden biri olan IRE1α’nın seçici bir inhibitörü olan MKC-3946 ile inhibisyonunun PANC-1 hücrelerinin tümörijenik özellikleri üzerindeki etkileri araştırılmıştır.

Materyal-Metot: MKC-3946’ün biyokimyasal etkinliği immünoblotlama ile değerlendirilmiştir. MKC-3946’ün PANC-1 hücrelerinin tümörijenik yeteneği üzerindeki etkileri WST-1 temelli hücre proliferasyon ölçümü, koloni oluşturma tahlili, yara iyileşme tahlili ile incelenmiştir.

Bulgular: MKC-3946 uygulaması PANC-1 hücrelerinin tümörijenik özelliklerini anlamlı düzeyde baskılamıştır.

Sonuç: IRE1α’nın farmakolojik olarak hedeflenmesi, pankreas kanserine yönelik olarak yeni bir terapötik bakış açısı sağlayabilir.

Anahtar Kelimeler

• MKC-3946
• IRE1α
• Pankreas kanseri
• UPR

Kaynakça

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